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Gastric parietal cells, also known as oxyntic cells, secrete hydrochloric acid in response to stimulation by acetylcholine (Ach) released from the vagus nerve, gastrin produced and secreted by gastric G cells, and histamine produced and secreted by enterochromaffin-like cells (ECL).
Gastrin is a heterogeneous hormone consisting primarily of 2 molecular forms differing in size and biological activity but both having a similar carboxy-terminal pentapeptide amide sequence. Stimulation of gastrin secretion is mediated by gastrin releasing peptide (GRP).[1, 2] Gastric antral distention and intragastric amino acids, amines, and calcium stimulate the release of GRP. Inhibition of hydrochloric acid secretion is mediated mainly by somatostatin (SST). Somatostatin is secreted by gastric D cells in response to increased gastric concentrations of HCl and suppresses gastrin secretion from gastric G cells, acid secretion from parietal cells, and histamine release by ECL cells.[4-6] In dogs, clearance of exogenously administered human gastrin by the kidney[7, 8] and lung has been demonstrated with an approximate half-life of 5 minutes. Increased serum gastrin concentrations can result from chronic pharmacologic suppression [H2-receptor antagonists (H2RA) and proton pump inhibitors (PPIs)] of gastric acid secretion in people and rats,[3, 11, 12] gastrinoma, Helicobacter pylori infection in humans, hepatic ischemia, and renal failure in humans and cats. Although H. pylori can stimulate gastrin secretion in canine cell culture systems, it does not appear to affect serum gastrin concentrations.
Gastrinomas are neuroendocrine tumors that secrete gastrin. Gastrinomas usually are located in the pancreas, but a gastrinoma has been documented in the duodenum of a dog. Dogs with gastrinomas typically develop vomiting, weight loss, anorexia, lethargy, diarrhea, polydipsia, and melena.[18-21] The presence of a gastrinoma may be suspected after documenting increased serum gastrin concentrations in a patient with compatible clinical signs in the absence of other conditions that increase serum gastrin concentrations. Serum gastrin concentrations in patients with gastrinoma may be 3–100 fold higher than normal, but in affected humans, two-thirds of patients have fasting gastrin concentrations <10 times normal.
Famotidine is an H2RA commonly used for symptomatic treatment of dogs exhibiting gastrointestinal (GI) signs. Famotidine suppresses gastric acid production by competitive inhibition of the histamine receptor on gastric parietal cells. The use of H2RAs and PPI in humans interferes with the diagnosis of gastrinoma by masking clinical signs.[23-25] Current recommendations for measuring serum gastrin concentration in human patients are to discontinue PPIs 7 days, and H2RAs for 48 hours, before blood sampling.
Because dogs with gastrinoma can exhibit gastrointestinal signs, some patients are treated with H2RAs before measurement of serum gastrin concentrations. Dogs admitted to our hospital often have been treated, sometimes for prolonged periods of time, with H2RAs such as famotidine. H2RAs, by virtue of their ability to suppress gastric acid secretion, may remove the negative feedback on gastrin secretion caused by luminal acid. They are thus likely to enhance gastrin secretion, which would falsely increase serum concentrations of gastrin. Although studies in human patients have confirmed H2RA-induced hypergastrinemia, this phenomenon has not been documented in dogs chronically treated with H2RAs. Knowing if hypergastrinemia is a consequence of chronic H2RA therapy in dogs has substantial clinical relevance in patients suspected to have gastrinoma. Whether or not H2RAs should be discontinued or whether or not there is a need for a “washout period” before measuring serum gastrin concentration in dogs has not been established. The purpose of this study was to determine the effect of long-term (14 days) famotidine treatment and its subsequent withdrawal on serum gastrin concentrations in dogs. An additional goal was to assess the stability of gastrin concentrations in serum samples held at room temperature before freezing. We hypothesized that famotidine treatment would increase serum gastrin concentrations in dogs and that discontinuation of famotidine would result in return of serum gastrin concentrations to baseline within 7 days. In addition, we hypothesized that room temperature storage of serum samples for 150 minutes would significantly decrease measured serum gastrin concentrations as compared to samples held at room temperature for <30 minutes.
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As hypothesized, mean serum gastrin concentrations peaked by day 3 of famotidine administration, but instead of remaining above basal concentrations, serum gastrin concentration had returned to baseline by day 14, the last day of famotidine administration, in all dogs. In a study of dogs treated with ranitidine for 7 days, basal serum gastrin concentrations peaked at day 4 after starting treatment, comparable to our results, and remained increased through day 7. In this study, fasting gastrin concentrations had returned to baseline 8 days after ranitidine was stopped, but there were no measurements of serum gastrin concentrations between days 7 and 15 so the time at which dogs returned to baseline could not be determined. Results of studies in humans of the effect of H2RAs on serum gastrin concentrations have been comparable to, or different from, our results. Earlier investigations showed administration of H2RAs for 8 days, or up to 29 days of continual daily dosing, resulted in consistently increased gastrin concentrations.[27, 28] In a more recent study, however, serum gastrin concentrations returned to baseline by day 14 of continual daily famotidine administration to human patients without evidence of H. pylori infection. In the earlier studies, the presence of H. pylori was not assessed. The interaction between H. pylori infection and H2RA administration has not been evaluated in dogs but gastrin concentrations were unaltered in dogs with Helicobacter infections.
Return of serum gastrin concentrations to baseline in people is thought to occur from tolerance to H2RAs. The mechanism of tolerance is not known, but is speculated to be a consequence of gastrin's trophic properties on gastric mucosa. Hypergastrinemia initially results in hypertrophy of ECL cells (days) and then hyperplasia (weeks), increasing histamine production. Increased numbers of histamine molecules then are able to competitively combine with receptors to stimulate acid production. Other suggested mechanisms of tolerance to H2RAs include upregulation of parietal cell receptors for other mediators, sensitization of H2 receptors, or alteration in H2 receptor turnover after chronic competitive inhibition. Consistent with the hypothesis of tolerance, abrupt discontinuation of HR2As causes rebound acid hypersecretion in humans as a result of the trophic properties of gastrin on ECL cells. The phenomenon of tolerance has not been investigated in veterinary patients.
A 12-hour fast before blood sampling was chosen due to constraints imposed by the blood sampling schedule after famotidine discontinuation, namely that dogs would have had to be fasted for 24 hours every other day for the last 8 days of the study period. The laboratory's reference interval for fasting serum gastrin concentration has been established for dogs fasted for >24 hours. The fact that dogs in our study were fasted for only 12 hours rather than 24 may have contributed to our observation of basal serum gastrin concentrations greater than the laboratory's reported reference interval in 9 of 18 dogs.
One important consideration when interpreting results of this study is that in people, gastrin secretion can fluctuate during the course of a day, and only a single sample was used to determine serum gastrin concentrations on each day of the study. Fluctuations in serum gastrin concentration also may have been a contributing factor in the increased basal serum gastrin concentration in 50% of our study animals. Perhaps a more accurate assessment of serum gastrin concentrations would have been to measure them in blood samples obtained hourly for 24 hours as has been performed in studies of humans. Despite this potential limitation, however, our findings of increased serum gastrin concentration in response to H2RA administration followed by decreased serum gastrin concentration in the face of continued administration are consistent with results of studies in humans and rats.
We were not able to establish a washout period of famotidine before measuring serum gastrin concentrations because gastrin concentrations returned to baseline while dogs were still receiving famotidine. Determining a washout period for an individual patient may be difficult for a number of reasons. First, owner compliance with oral medication administration is variable and can be poor, making it difficult to predict when famotidine actually was administered and withdrawn from a patient. Second, although mean serum gastrin concentration at 14 days was not significantly different from baseline, there was variability in the time at which serum gastrin concentration returned to baseline among individual dogs. Finally, owners also may administer other over-the-counter medications, such as antacids, that might also alter gastric acid-gastrin physiology. Although it might be ideal to measure serum gastrin concentrations in the absence of famotidine treatment, our data suggest that famotidine therapy is unlikely to confuse interpretation because none of our study patients developed serum gastrin concentrations typical of dogs with gastrinoma, and dogs on famotidine for over 11 days actually had serum gastrin concentrations within reference ranges.
Our finding that serum gastrin was not stable when serum samples were stored at room temperature for 150 minutes as compared to 30 minutes after blood sampling is consistent with results of studies of gastrin stability in people. Recommendations made by the authors of one study were that serum should be frozen at −70°C as soon as possible before analysis. Serum gastrin concentrations in samples stored at room temperature for 24 hours decreased by almost 50%. Surprisingly, gastrin concentrations in samples stored for 24 hours at 4 and −6°C declined by >10%. The average decrease in serum gastrin concentration in our study samples maintained at room temperature for over 2 hours before freezing was 20%. Dogs in which serum gastrin concentrations are only marginally increased, or at the lower end of the spectrum for a gastrinoma, may appear to have normal or only slightly increased gastrin concentrations if the sample is inappropriately handled. This could result in an inappropriate dismissal of gastrinoma as a differential diagnosis for a particular patient. Based on our findings, it is recommended that serum samples be frozen as quickly as possible after collection.
Finally, the results of our study raise an important and clinically relevant question, which is whether or not administration of famotidine for more than 14 days is effective in suppressing gastric acid production. Although Komazawa et al documented a return of serum gastrin concentrations to normal in humans treated with famotidine for 14 days, there appeared to be some continued suppression of acid secretion. We did not measure gastric acid secretion or intraluminal pH in our study subjects and thus cannot make a definitive statement as to the efficacy of long-term famotidine treatment in suppression of acid secretion in dogs. Based on results of a recent study in dogs in which intragastric pH was >3 for only a short percentage of time during a 7-day famotidine treatment, the utility of famotidine for long-term acid suppression would seem to warrant investigation.