Review Article: Strategies to Determine Whether Hypergastrinaemia Is Due to Zollinger-Ellison Syndrome Rather Than a More Common Benign Cause

S.V.M. Murugesan; A. Varro; D.M. Pritchard


Aliment Pharmacol Ther. 2009;29(10):1055-1068. 

In This Article

Causes of Hypergastrinaemia

The several different causes of hypergastrinaemia can be classified into two main groups, as illustrated in Table 1. The main division is based on an assessment of the pH of gastric juice. Juice for this purpose can be obtained either by aspiration using a nasogastric tube or by suction at the time of endoscopy. Luminal gastric pH in fasted normal subjects is ≤2. Following this assessment, the cause of many cases of hypergastrinaemia, particularly those associated with hypochlorhydria and atrophic gastritis can relatively easily be determined.

Hypergastrinaemia Associated with an Elevated Gastric pH (pH > 2)

The most common cause of a markedly elevated fasting serum gastrin concentration is chronic atrophic gastritis, due to either autoimmune gastritis, which is often associated with pernicious anaemia or secondary to chronic H. pylori infection.[17] Both these conditions lead to hypochlorhydria or achlorhydria, as a result of loss of acid secreting parietal cells. This resulting loss of feedback inhibition causes unopposed gastrin release and this causes hyperplasia of ECL cells. In some patients, particularly those with autoimmune chronic atrophic gastritis, this can progress and result in the development of type I gastric ECL-cell neuroendocrine (carcinoid) tumours.[18,19] Most of these lesions are small and require no treatment, but lesions greater than 1 cm in diameter may require some form of surgical intervention. The diagnosis of atrophic gastritis can be made by demonstrating an elevated gastric juice pH and atrophy on gastric corpus biopsies. In addition, the presence of gastric parietal cell or intrinsic factor antibodies, anaemia, high MCV (mean cell volume) and a low serum vitamin B12 level support the diagnosis of autoimmune gastritis (pernicious anaemia).

Chronic atrophic gastritis secondary to chronic H. pylori infection is also associated with an elevated gastric pH and the diagnosis can be confirmed by establishing the presence of atrophy (and sometimes H. pylori organisms) on corpus biopsies. H. pylori serology may be positive even though evidence of current infection cannot be found.

The degree of hypergastrinaemia in both types of gastric atrophy can range from mild to severe, although moderate hypergastrinaemia (< 10 times upper limit of normal) is most often found.[20]

Hypergastrinaemia Associated with an Acidic Gastric pH (pH ≤2)

Hypergastrinaemia associated with an acidic gastric juice pH is often caused by gastrin secreting tumours. Zollinger and Ellison first described the clinical syndrome of multiple gastric and duodenal ulcerations and diarrhoea associated with endocrine tumours of the pancreas.[21] Roy et al. found only 1 patient out of 1221 with ZES who had a basal gastric pH > 2.[6] ZES may be sporadic or associated with multiple endocrine neoplasia (MEN) type-1 (which is characterized by the presence of adenomas in the pituitary gland, parathyroid glands and pancreatic islet cells). MEN type-1 is inherited as an autosomal dominant trait (Wermer's syndrome) and results from the loss of menin, a tumour suppressor gene located at chromosome 11q13.[22] The prevalence of MEN type-1 in patients with ZES has been reported to be between 10 and 40% and there are differences in clinical features and prognosis compared with sporadic ZES.[23,24,25,26] The prevalence of ZES in MEN type-1 has been reported to be around 21-70%.[23,26,27,28] Gastrinomas related to the MEN type-1 syndrome often tend to be multifocal, small (less than 2 cm) and are more frequently localized in the duodenal mucosa than sporadic gastrinomas. Hence, the duodenum should be the first site to be investigated when attempting to localize these tumours. The gastrinomas associated with the sporadic type of ZES are more often located in the pancreas (50-60%) and are also more frequently solitary and larger in size. Some reports have suggested an increased rate of malignant transformation and metastasis associated with sporadic compared to MEN type-1 gastrinomas, although this has not been confirmed in follow up studies.[29,30,31,32] Prolonged hypergastrinaemia particularly that associated with MEN type-I gastrinomas can also lead to ECL-cell hyperplasia and in some cases subsequent ECL-cell neuroendocrine (carcinoid) tumour development (type-II gastric carcinoids). Type II gastric carcinoid tumours occur in about 20% of MEN type-1 associated gastrinoma cases as compared to about 1% of sporadic gastrinoma cases.[33,34]

Other Causes of Hypergastrinaemia

In addition to the important causes of hypergastrinaemia outlined above, a number of other much rarer conditions can cause hypergastrinaemia ( Table 1 ). However, many of these are apparent from the clinical history.

Post Vagotomy. Vagotomy results in decreased acid secretion by loss of vagal mediated acetylcholine stimulation of gastric parietal cells. The resulting hypergastrinaemia is usually modest (~200 pg/mL or ~100 pM). The source of gastrin in this situation is antral, as hypergastrinaemia is abolished following antrectomy.[17,35]

Excluded Gastric Antrum. Korman et al., first reported a patient with recurrent peptic ulceration due to an excluded gastric antrum following Billroth II partial gastrectomy. This occurred due to incomplete excision of the antrum from the detached duodenum. Exposure of residual antral tissue in the duodenal stump to neutral or alkaline juice results in increased gastrin secretion, leading to hypergastrinaemia and subsequently increased gastric acid secretion. The resultant hypergastrinaemia is usually mild to moderate (2 to 3 times the upper limit of normal),[36,37] but the secretin stimulation test shows a marked fall in serum gastrin concentration rather than the increase usually observed with gastrinoma.[38] Owing to changes in surgical practice, this diagnosis is now extremely rare.

Chronic Renal Failure. Gastrin is cleared from the circulation partly by renal metabolism. Hence hypergastrinaemia is often seen in patients with chronic renal failure[39] with about 10% of patients exhibiting fasting serum gastrin concentrations in the range often seen in ZES.[39] In one study involving 89 patients, the fasting serum gastrin concentration was elevated in all patients, with a mean serum gastrin concentration of up to four times the upper limit of normal. The degree of hypergastrinaemia was proportional to the degree of renal impairment. In another study, hypergastrinaemia was more marked in those patients who were also infected with H. pylori.[40] Haemodialysis was initially found not to lower serum gastrin concentrations, but renal transplantation did result in normalization of previously elevated serum gastrin concentrations.[41] However, a more recent study demonstrated reduction of previously elevated gastrin concentrations following 3 months of dialysis, although values were still higher than controls.[42]


Pyloric Obstruction. Feurle et al. studied changes in gastric acid output and serum gastrin concentrations in patients with pyloric obstruction secondary to peptic ulcer disease. These authors reported that in addition to a circadian variation in serum gastrin concentration (with four major peaks found at 08-10, 12, 14-17 and 20.00 h and the lowest concentration being between 03 and 07.00 h), patients with pyloric obstruction had markedly increased serum concentrations of gastrin, which decreased within 8 days of relief of obstruction. This suggests that additional mechanical factors cause an increase in serum gastrin concentration.[43] This and other reports have shown elevations in serum gastrin concentrations in patients with pyloric obstruction from around twice the upper limit of normal to concentrations of up to 800 pg/mL (~ 380 pm).[44]


Other Miscellaneous Conditions. A single study has reported a small but statistically significant increase (mean from 47.5 to 74.4 pg/mL) in fasting serum gastrin concentration in patients with Crohn's disease, despite a lower rate of H. pylori infection. No differences were however found in patients with ulcerative colitis compared to normal controls.[45] Increased fasting serum gastrin concentrations have been reported in HIV-positive patients without overt AIDS compared with HIV-positive patients with overt AIDS.[46] The underlying mechanisms are currently unclear. Although some older studies have suggested an association between hypercalcaemia and hypergastrinaemia, a study of 52 consecutive patients with primary hyperparathyroidism showed that alternative causes, such as MEN1, H. pylori infection or PPI use rather than hypercalcaemia per se were responsible for hypergastrinaemia in all cases.[47]


Falsely Elevated Serum Gastrin Concentration. A case report by Romeo et al. describes a patient with a falsely elevated serum gastrin concentration which led to an initial misdiagnosis of ZES. Hypergastrinaemia was later found to be due to the interference of the patient's markedly lipaemic serum sample with the gastrin radioimmunoassay.[48] This phenomenon may, however, have resulted from the use of a non-standardized assay. Most laboratories currently use standardized assays and do not appear to experience such interference when measuring serum gastrin concentrations.[15]