Proton pump inhibitors,osteoporosis, and osteoporosis-related fractures

Proton pump inhibitors (PPIs) are among the most commonly prescribed medications today with an excellent short-term safety profile. Recently, a number of studies from a variety of data sources have reported an association between PPI use and hip fractures. However, there is not yet any direct evidence of a causal link between PPI use and the development of hip fracture. In the following paper, we will review the recent studies which have described this association between PPI use and hip fracture, and discuss the evidence supporting the likelihood of this association being causal, using data from previous work on the effects of surgical and pharmacological inhibition of gastric acid secretion on calcium absorption and bone mineral density. We will conclude by summarizing the current state of evidence on the relationship between gastric acid inhibition and the risk of fracture, and suggest management strategies for patients who require the long-term use of gastric acid inhibiting medications who also may be at risk for metabolic bone disease and fracture.     

Polymorphism in the C-reactive protein (CRP) gene affects CRP levels in plasma and one early marker of atherosclerosis in men: The Health 2000 Survey

The gastrointestinal hormone gastrin is measured in plasma in physiological, pathophysiological and diagnostic investigations. In the diagnosis of hypergastrinaemic diseases such as gastrinomas and gastric achlorhydria, measurement of gastrin concentrations in circulation is crucial. Gastrin circulates, however, not as a single peptide but as a mixture of peptides of different lengths and amino acid derivatizations. Moreover, in hypergastrinaemia the peptide pattern changes. Consequently, diagnostic gastrin measurements require immunoassays that recognize the pathological plasma patterns, which are characterized by a predominance of the large peptides (gastrin‐34 and gastrin‐71) and less, if any, of the shorter main form of gastrin in normal tissue, gastrin‐17. Alternatively, and in specific cases, “processing‐independent assays” (PIA) for progastrin may be considered, since hypersecreting gastrin cells also release substantial amounts of biosynthetic precursors and processing intermediates. Recently, gastrin kits that do not take the pathological plasma patterns into account have been marketed and may miss the diagnosis. Therefore, proper diagnosis of gastrinomas and other hypergastrinaemic diseases requires insight into cellular gastrin synthesis and peripheral metabolism, and also into the design of useful immunoassays. This review discusses the art of measuring gastrin in plasma with adequate diagnostic specificity.     

Morphological findings of different areas of gastric mucosa in patients with achlorhydria,extreme hypochlorhydria,Normochlorhydria and their relationship to serum gastrin level: Evidence for two different types of gastritis

Summary The morphological changes of gastric mucosa taken from different areas have been studied in patients of approximately the same age with achlorhydria, extreme hypochlorhydria and normochlorhydria. The serum gastrin level and parietal cell antibodies were determined in the achlorhydric patients. In the latter the diffuse gastritis was localized in the corpus-fundic area, while the changes in the antral region were few and occurred mostly in the superficial zone. In normochlorhydric patients however, the diffuse gastritis was localized in the antral region, with only few changes at the corpus-fundic area. In patients with extreme hypochlorhydria either the fundic or the antral region was involved. Besides the diffuse gastritis intestinal metaplasia, pseudopyloric metaplasia, and atrophy of mucosa were also observed, although much less commonly. The increase of gastrin level could not be related to a definite morphological pattern in the gastric mucosa.It can be assumed that each of the two types of gastritis has a different natural history; the antral site of gastritis cannot be transformed into the fundic site, nor can the fundic site be transformed into the antral site.Parts of this study were presented at the Fifth World Congress of Gastroenterology, Mexico, 1974     

Does High Gastric Cancer Risk Associated with Low Serum Ferritin Level Reflect Achlorhydria? An Examination via Cross-sectional Study

With respect to the inverse association of serum ferritin level (SFL) with the risk of gastric cancer (GC) observed in some recent epidemiologic studies, possible mediation by achlorhydria as well as atrophic gastritis (AG), both of which are strongly associated with GC risk at not only the individual but also the population level, was examined in a cross-sectional study of 634 men aged 40 to 49 years randomly selected from 5 populations in Okinawa, Iwate, Nagano, Akita and Tokyo. AG and achlorhydria were serologically diagnosed based on the criteria of pepsinogen (Pep) I level <70 ng/ml and Pep I/Pep II ratio <3.0, as described previously, and a serum gastrin level of over 140 pg/ml, respectively. In the results, while the mean SFL for all the subjects differed significantly by area, similar areal differences in SFL were also found even when only the non-AG cases were considered. However, both of the above differences were eliminated with the exception of those between Okinawa and each of the other 4 areas, when adjustments were made for medical histories of diabetes mellitus, ulcers and liver disease, body mass index and γ-glutamyltranspeptidase level. Therefore, no correlation among the 5 areas was observed between the adjusted areal mean SFLs and GC mortality in either case. However, in 17 (45%) achlorhydric cases identified among the 38 subjects with severe AG, which were further discriminated with stricter criteria (Pep I <30 ng/ml and Pep I/Pep II ratio <2.0), their averaged SFL was significantly lower than the values for the non-AG cases (3.78 vs. 4.64 In(ng/ml), P<0.001) and mild/moderate AG cases (3.78 vs. 4.47 ln(ng/ml), P<0.01), while the differences were not significant with respect to the other 21 (55%) severe AG cases without achlorhydria. Thus, it is suggested that the negative association of SFL, for which no mechanism has been shown in cancer etiology, with GC risk is indirect, since both of them are associated primarily with achlorhydria found among the severe AG cases. Moreover, areal mean SFLs, which are not determined only on the basis of the prevalence of achlorhydric AG cases, could not be related to GC mortality rates, suggesting that no direct association exists at the population level either.     

The Effect of X-Irradiation on Gastric Secretion in the Intact Guinea-Pig

Volume, pH, and total acidity of the basal and of the stimulated gastric secretion were measured in guinea-pigs before, and at appropriate intervals after, x-irradiation to the stomach area. A great reduction of the stimulated acidity and acid output was found. It reached a maximum between the second and the fourth week after irradiation. Thereafter the total acidity increased gradually, but, 56 weeks after irradiation, it still remained significantly below the normal (p < 0.05). The volume was lowered to a lesser extent.     

Increased tissue concentrations of the gastrin precursor in patients treated with omeprazole

The main form of gastrin in antral mucosa, the amidated heptadecapeptide G17, is generated from an inactive precursor, progastrin, by steps involving endopeptidase cleavage and amidation. Gastrin cells are normally inhibited by gastric acid and in this study we have examined how suppression of acid by treatment with omeprazole for 6-8 weeks influences gastrin production in patients with oesophagitis. Plasma concentrations of total amidated gastrins in the fasting state increased from 18 to 43 pmol l-1; assays specific for G17-immunoreactivity indicated that the plasma concentrations of this form increased from 6 to 12 pmol l-1. In endoscopic biopsies of antral mucosa there was no change with omeprazole treatment in the concentrations of total amidated gastrins, or their immediate precursors, the Gly-extended gastrins. However, assays using an antibody that reacts with progastrin, together with size exclusion chromatography, indicated that tissue progastrin concentration increased 6-fold. The data suggest a modest net increase in gastrin production with omeprazole-treatment; because the ratio of tissue concentrations of total amidated gastrins to Gly-extended gastrins did not change, it would seem that the amidating capacity of the gastrin cell was maintained. However, the increase in progastrin concentrations suggests a relative failure of the initial steps of post-translational processing, and consequently that in certain circumstances endopeptidase cleavage of progastrin may be rate limiting.     

Intestinal Metaplasia,Not Atrophy or Achlorhydria,Creates a Hostile Environment for Helicobacter pylori

A 54-year-old man with dyspepsia, Helicobacter pylori-associated chronic active atrophic gastritis without intestinal metaplasia, and hyperplastic gastric polyps was followed up for 1 year after H. pylori eradication with sequential endoscopic gastric mucosal mapping and gastric function tests. Eradication of H. pylori by triple therapy resulted in the histologic resolution of gastritis. However, the patient's condition, gastric function, and morphology of the polyps were not affected. This case illustrates that: a) in the absence of intestinal metaplasia, H. pylori can infect the stomach with gastric atrophy; b) the absence of acid does not preclude H. pylori infection; c) advanced atrophic gastritis may be an irreversible condition; and (d) the neutrophilic infiltrate in hyperplastic polyps is independent of the presence of H. pylori.     

Pernicious Anaemia,Intragastric Bacterial Overgrowth,and Possible Consequences

Intragastric bacterial colonization is well known in pernicious anaemia (PA), but its consequences have rarely been investigated. We have studied the clinical history, blood samples, and endoscopic biopsies from the stomach and duodenum of 80 patients with PA. In a random subgroup of 22 patients gastric juice was collected for aerobic culture and for estimation of nitrate, nitrate-reducing bacteria, nitrite, and N-nitrosamines; duodenal juice was studied in parallel in eight of these subjects. Gastric and duodenal juice had high bacterial counts; faecal organisms were found in 14 patients. The mean count of nitrate-reducing bacteria was significantly higher than in a control group of patients with peptic ulcer disease (p < 0.001), as was the nitrite concentration (p < 0.001). Thirty-three of the 80 patients had gastric dysplasias; 1 early gastric carcinoma was also found. Duodenitis was present in 39 out of 80 cases, in 6 associated with partial villous atrophy. A history of malabsorption and/or chronic intermittent diarrhoea was obtained significantly more often from patients with duodenitis. Four patients developed acute gastroenteritis shortly before or during the time of the study, two having a salmonella infection. Bacterial overgrowth in PA may be facilitated by altered immunological conditions, since low serum levels of IgA and IgG were found in this patient group.     

Pernicious anemia： What are the actual diagnosis criteria？

A gastric intrinsic factor output under 200 U/h after pentagastrin stimulation (N > 2000 U/h) is specific for pernicious anemia. The other findings are either variable or non specific. Serum intrinsic factor antibodies, considered as specific in general practice, are present only in half of the patients with pernicious anemia. In their absence, since the disappearance of the Schilling tests, the gastric tubage currently used for the study of gastric acid secretion, is obligatory for the simultaneous study o...     

Impaired skeletal health in patients with chronic atrophic gastritis

Objective: In chronic atrophic gastritis (CAG), destruction of gastric parietal cells causes anacidity and hypergastrinemia. Use of proton pump inhibitors, which also induces gastric anacidity, is associated with increased fracture rates. Our objectives were to study possible differences in bone mineral density (BMD) and bone quality in patients with CAG compared to controls.

Material and methods: We performed a cross-sectional study on 17 CAG patients aged 54?±?13 years and 41 sex- and age-matched controls. Lumbar and femoral BMD and bone quality assessed by lumbar trabecular bone score (TBS) were measured by DXA, and bone material strength (BMS) by microindentation of the tibia. Serum bone markers (CTX, P1NP, sclerostin, osteocalcin, OPG, RANKL) were analyzed.

Results: We found lower lumbar BMD Z-score (?0.324?±?1.096 versus 0.456?±?1.262, p?=?0.030), as well as a higher frequency of osteoporosis at the lumbar spine (p?=?0.046) and osteopenia at total hip (p?=?0.019) in patients compared to controls. In a post hoc subgroup analysis, we observed that the differences were confined to the male patients. TBS also tended to be lower in male patients (p?=?0.059), while BMS did not differ between the groups. Osteocalcin, sclerostin, OPG, and OPG/RANKL ratio were lower in patients compared to controls, while CTX and P1NP did not differ between the groups.

Conclusions: We observed lower lumbar BMD, increased frequency of osteopenia and osteoporosis in male, but not female patients with CAG. Bone markers suggest a decrease in bone formation and increased bone resorption in CAG patients compared to controls.