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

Abstract and Introduction


Background: As there is considerable overlap between the fasting serum gastrin concentrations found in Zollinger-Ellison syndrome and various common conditions such as Helicobacter pylori infection and acid suppressing medication use, establishing the cause of hypergastrinaemia in individual cases can sometimes be difficult.
Aim: To review the causes of hypergastrinaemia and the role of additional non-invasive investigations in hypergastrinaemic patients.
Methods: Review of articles following a Pubmed search.
Results: As gastrinomas may cause serious complications and be potentially life threatening, investigation of hypergastrinaemic patients should particularly focus on confirming or refuting the diagnosis of Zollinger-Ellison syndrome. Establishing the cause of hypergastrinaemia may be difficult when there is only a mild-to-moderate elevation of fasting serum gastrin concentration and concurrent treatment with proton pump inhibitor drugs and the presence of H. pylori infection can both confuse the clinical picture. A variety of provocative tests are therefore useful for establishing whether a hypergastrinaemic patient has a gastrinoma and current evidence suggests that the secretin test should be used first line.
Conclusions: We suggest an algorithm for the investigation of patients found to have an elevated fasting serum gastrin concentration and address the roles of gastrin stimulation tests in current clinical practice.


Hypergastrinaemia (defined in most publications as a fasting serum gastrin concentration of > 100 pg/mL or > 47.7 pM) is frequently encountered in modern clinical practice. The upper limit of normal was set at the fasting gastrin concentration greater than two standard deviations above the mean in cohorts of healthy subjects and this has been confirmed in Helicobacter pylori negative subjects in a more recent study.[1] Older subjects show slightly higher fasting serum gastrin concentrations than younger individuals, but in the absence of H. pylori infection and gastric autoantibodies, these values are usually still within the normal range.[2]

Fasting serum gastrin concentration is measured specifically to investigate whether clinical conditions such as complicated peptic ulcer disease or persistent diarrhoea are caused by the Zollinger-Ellison syndrome (ZES). However, increasingly, serum concentration of gastrin is also being measured as part of a gut hormone profile (often including chromogranin A and other hormones such as somatostatin, glucagon and vasoactive intestinal peptide) to investigate possible or confirmed neuroendocrine tumours or multiple endocrine neoplasia type I. In the UK, such assays are performed at two supraregional laboratories in London and Belfast. The proportion of requests for gut hormone profiles rather than individual hormone measurements and the annual number of requests for gut hormone measurements both appear to be increasing substantially (Prof M.A. Ghatei, personal communication). Clinicians are therefore not infrequently required to interpret and determine the cause of elevated fasting serum gastrin concentrations. The main clinical requirement is usually to establish whether an elevated serum gastrin level is due to a gastrinoma, which is a potentially life-threatening condition or whether there is a less serious underlying cause.

There are a number of potential causes of hypergastrinaemia, many of which are nontumorous and are associated with an excellent prognosis (see Table 1 ). A fasting serum gastrin concentration greater than 1000 pg/mL (477 pM)[3,4,5,6] in the presence of an acidic gastric juice pH (≤2) is highly suggestive of ZES and subsequent investigations in this scenario should therefore initially be targeted at tumour localization. However, many patients present with a fasting serum gastrin concentration that is not elevated to this degree. As there is considerable overlap between the fasting gastrin concentration found in ZES and in much more common benign conditions such as H. pylori infection or proton pump inhibitor use, a definitive diagnosis of ZES is often not possible without additional investigations.[4] Approximately 68% of patients with ZES have fasting serum gastrin concentrations between 100 and 1000 pg/mL (47.7-477 pM) and 0.3-3% even exhibit normal fasting serum gastrin concentrations, whereas very high concentrations (> 100 times upper limit of normal) are only found in 4.9-9% of ZES patients.[4] In patients with confirmed ZES, however, the severity of fasting serum gastrin elevation at presentation has been shown to correlate with size and site of tumour and with the presence of metastases, all of which are independent prognostic indicators.[7]