Diarrhea, Weight Loss, and an Elevated Gastrin: A Case Report Open Access

Gastrin is one of the most clinically relevant hormones of the digestive system and is released by the G cells of the antrum of the stomach to stimulate gastric acid secretion as well as to facilitate proliferation of the gastric epithelial cells, tissue remodeling, and angiogenesis [1]. Hypergastrinemia is abnormal gastrin production seen in some clinical and diseased states and is defined by a gastrin level greater than 100–150 pg/mL [2]. Hypergastrinemia can be subdivided into appropriate and inappropriate acid secretion with appropriate occurring under neutral stomach pH and inappropriate occurring in the presence of an already acidic stomach pH of <4. An inappropriately elevated gastrin with an acidic stomach promptly triggers clinicians to evaluate for Zollinger-Ellison syndrome (ZES). We present a case of inappropriate gastrin secretion secondary to a less common syndrome of G-cell hyperplasia. The CARE checklist has been completed by the authors for this case report, attached as online supplementary material (for all online suppl. material, see https://doi.org/10.1159/000545714).

A 51-year-old female presented with a 3-month history of diarrhea and 55-pound weight loss. Past medical history included a history of refractory gastroesophageal reflux requiring Nissen fundoplication 18 years prior on chronic PPI therapy with esomeprazole 40 mg twice daily since her operation. Prior workup included a negative GI pathogen panel as well as EGD with gastric/antral and small bowel biopsies, colonoscopy with biopsies, and MR enterography which were unremarkable. A urinary 5-HIAA was normal. She had undergone treatment for her diarrhea with Imodium without a change in symptoms and had recently started Lomotil four times daily with a minimal subjective improvement in stool consistency. On physical exam she appeared emaciated and fatigued with a normal abdominal examination.

Further workup included a GI pathogen panel which was positive for norovirus. The patient was given a 7-day trial of nitazoxanide without a change in stool symptoms. Stool electrolytes showed Na 85, K 55, osmolality 310, and an osmotic gap of 30 consistent with secretory diarrhea. A 48-h fecal fat study revealed 500 g stool and 51 g of fat per 24 h. Flexible sigmoidoscopy was normal with biopsies showing no inflammatory damage and negative staining for CMV. A gastrin level off her PPI was 589 pg/mL (normal reference level <100 pg/mL) with a chromogranin level of 307 ng/mL (normal reference level <93 ng/mL).

Given her elevated gastrin, steatorrhea, and evidence of a secretory diarrhea a diagnosis of ZES was considered. EGD with EUS was performed which was significant for a gastric pH of 2 and gastric and duodenal biopsies revealed no evidence of atrophic gastritis or celiac disease. On EUS, the pancreas appeared normal with no evidence of mass. A 4-mm lesion was identified adjacent to the second portion of the duodenum raising a question of a lymph node versus a small mass. Fine needle aspiration was performed, and histology was negative for neoplasm. Because of ongoing concern for a gastrinoma a DOTATATE PET scan was performed and was negative. A secretin stimulation test was also performed and was unremarkable.

Given the concern for possible G-cell hyperplasia, a standardized test meal was performed with PPI held for 7 days, H2 blocker for 3 days, and Creon for 1 day. Gastrin level was measured at baseline and at 15, 30, 45, 60, 90, 120, and 180 min after test meal ingestion (Fig. 1). Baseline gastrin level was normal at 45 pg/mL which differed from previously identified hypergastrinemia. An 8-fold increase in gastrin after the standardized meal supported the diagnosis of G-cell hyperplasia and spoke against gastrinoma. She continued to have refractory heartburn despite BID PPI therapy as well as diarrhea and weight loss on high-dose Creon. Given her ongoing symptoms, negative radiographic and endoscopic evaluation, failure of response to medical therapy, and concern for either G-cell hyperplasia or localization study-negative gastrinoma she was referred for surgical consultation. It was discussed with the patient that she was at high risk for post-gastrectomy syndromes due to her female sex and thin body habitus. She elected to proceed with duodenal and pancreatic evaluation with intraoperative ultrasound and manual palpation which did not reveal an underlying tumor. Antrectomy with Billroth II was therefore performed for treatment of G-cell hyperplasia with pathology showing an increased G-cell population (Fig. 2). Follow-up gastrin level on postoperative day one had decreased 12 pg/mL. Following her antral surgery, her diarrhea resolved immediately and she proceeded to regain 60 pounds over the next 12 months.

An understanding of pathophysiology of gastrin and acid secretion and appropriate versus inappropriate hypergastrinemia is needed to identify cases of potential G-cell hyperplasia or classical ZES and to perform further diagnostic testing and treatment. Gastric acid is produced by parietal cells in response to 3 neurohumoral signals: acetylcholine from vagal nerve endings, gastrin from G cells in the antrum, and histamine from enterochromaffin-like cells. Gastrin is initially synthesized as pro-gastrin within G cells in the antrum and cleaved into active gastrin in the stomach. Gastrin release is triggered by food intake with proteins and amino acids serving as primary triggers. Gastrin is inhibited by somatostatin secreted from D cells in the stomach lining, fasting state, or increased stomach acidity [3].

The distinction of appropriate versus inappropriate hypergastrinemia is important and helps with delineation of cause. In cases of PPI use, H. pylori infection, atrophic gastritis, renal failure, or vagotomy, there is decreased acid production in the stomach and a physiologic, appropriate increase in serum gastrin. Decreased acid production is verified with a gastric pH of 4 or greater on gastric aspirate [4, 5]. Inappropriate hypergastrinemia is defined by elevated gastrin levels in the face of gastric acidity with pH <4. There are 4 primary causes of inappropriate hypergastrinemia: ZES, antral G-cell hyperplasia, gastric outlet obstruction, and retained antrum syndrome. Gastric outlet obstruction causes antral distension stimulating cholinergic reflexes, release of acetylcholine, and parietal and G-cell stimulation. Retained antrum syndrome is an uncommon occurrence and can be ruled out with review of surgical records and/or endoscopy with biopsy. Further radiographic and diagnostic testing can help distinguish ZES from antral G-cell hyperplasia.

Friesen et al. [6] outlined the differences in gastrin response to secretin stimulation testing and a standardized test meal between patients with duodenal ulcer, G-cell hyperplasia, and classic ZES. To summarize, basal serum gastrin cannot distinguish between G-cell hyperplasia and ZES. In G-cell hyperplasia, basal serum gastrin can be within the normal range or elevated but is generally under 1,000 pg/mL when elevated [7]. Secretin stimulation test demonstrates no significant change in serum gastrin in G-cell hyperplasia and a paradoxical hyperresponse in cases of ZES with serum gastrin rises over 110 pg/mL or greater. Assessment of gastrin response to a standardized test meal originally described by Friesen was composed of a high protein breakfast of three medium eggs, two slices of bacon, two slices of toast and 8 ounces of 2% milk. In total, it contains 34.5 g of protein, 26.6 g of fat, and 41.1 g of carbohydrate and can be approximated by 2 breakfast sandwiches and a glass of milk. Blood for serum gastrin is drawn prior to the meal and at 15, 30, 45, 60, 90, 120, and 180 min after stimulus. Normal individuals will have a mean maximal increase of gastrin of 120%, whereas patients with classic ZES have only a 40% mean maximal rise and patients with G-cell hyperplasia have a 300% rise. Of note, patients must stop PPI 7 days prior, H2 blocker 3 days prior, and pancreatic enzyme supplements the day of standard test meal.

Our patient’s hypergastrinemia associated with refractory reflux, diarrhea with profound steatorrhea associated with significant weight loss, extensive negative evaluation for gastrinoma, classic positive gastrin response to a standardized test meal, and marked clinical response to antrectomy support G-cell hyperplasia as the underlying diagnosis. A similar case of gastric acid hypersecretion presenting as diarrhea, weight loss, and acid reflux has been reported [8], although that patient did not have histopathologic diagnosis and responded to PPI therapy. Other cases of G-cell hyperplasia requiring antrectomy have primarily involved persistent peptic ulcers [9, 10]. While steatorrhea is a known consequence of gastrinoma, this seems to be the first reported association with G-cell hyperplasia.

In summary, the diagnosis of G-cell hyperplasia needs to be considered in patients with symptoms suggestive of gastrinoma with negative imaging studies and secretin stimulation test. A standardized test meal with serial gastrin levels can help distinguish G-cell hyperplasia. If history and testing are consistent with G-cell hyperplasia, antrectomy should be strongly considered.

This retrospective review of patient data did not require ethical approval in accordance with local/national guidelines. Written informed consent was obtained from participant for publication of the details of their medical case and any accompanying images.

The authors have no conflicts of interest to declare.

This study was not supported by any sponsor or funder.

R.G.A.: study design, data extraction, and manuscript preparation and submission. J.C.C.: pathology slide review and manuscript review. G.B.T.: surgical performance and manuscript review. G.L.A.: study design and manuscript review.

All data generated or analyzed during this study are included in this article and its online supplementary material. Further inquiries can be directed to the corresponding author.