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

Disclosures

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

In This Article

Common Clinical Situations Which Can Cause Hypergastrinaemia and Potentially Mask the Diagnosis of Zollinger-Ellison Syndrome

As already discussed, the diagnosis of ZES can be made relatively easily when the fasting serum gastrin concentration is > 100 times the upper limit of normal, in the presence of an acidic gastric juice (pH< 2). However, frequently, the diagnosis is not this straightforward and a recent large study suggested that difficulties in reaching a diagnosis are often encountered when fasting serum gastrin concentrations are between > 10 and < 100 times the upper limit of normal (mild-to-moderate hypergastrinaemia).[4] In addition, as gastrinomas are often small and multicentric, imaging studies may not be helpful in establishing the diagnosis. However, as these tumours can metastasize and as they may lead to serious complications particularly as a result of peptic ulceration, it is important to investigate whether ZES is the cause of each case of hypergastrinaemia.

Two extremely common clinical scenarios, first, the use of acid suppressant medication and second, the presence of H. pylori infection may lead to an increase in fasting serum gastrin concentrations. These situations can therefore make interpretation of elevated gastrin test results difficult. Several important questions are often asked when patients are taking proton pump inhibitor (PPI) or H2-Receptor antagonist (H2RA) medications, in particular, if PPIs should be discontinued (with the worrisome possibility of precipitating complicated peptic ulcer disease) and if so, for how long prior to measuring serum gastrin concentrations.

PPI and H2RA Drugs

PPIs and H2RA drugs have been well documented to cause mild-to-modest elevations in fasting serum gastrin concentrations. This is a result of inducing hypochlorhydria, which in turn causes loss of the normal negative feedback inhibition of gastrin secretion. However, the degree of elevation of fasting serum gastrin concentration is usually only modest (less than three times the upper limit of normal) and only about 2% of people on PPIs develop fasting serum gastrin concentrations greater than 400 pg/mL.[49] PPIs do not however appear to cause a further increase in fasting serum gastrin concentration in patients with ZES.[50] Lamberts et al. reported moderate hypergastrinaemia (from 74 to 145 pg/mL) in 74 patients after 3 months of taking omeprazole[51] and in a subsequent study reported a median elevation in serum gastrin concentration from 137 (pre-treatment level) to 293 pg/mL after one year of treatment with omeprazole. Interestingly, no further changes were noted during a further 8-year follow-up. The relatively high baseline serum gastrin concentrations reported in these studies were felt to be secondary to previous ranitidine treatment.[49,52] Koop et al. also demonstrated mild-to-moderate increases in fasting serum gastrin concentrations following PPI treatment and found a close correlation between pre-treatment and week 4 serum gastrin concentrations irrespective of the dose of omeprazole used. Again, no subsequent increases in serum gastrin concentration were observed during long-term (12 months) drug use.[53] Elevated serum gastrin concentrations were also found in 73% of 113 children treated with PPI for 1 year.[54] Alternate day regimens of PPI appear to be less susceptible to inducing hypergastrinaemia.[55]

Elevated serum gastrin concentrations take about 1 week to return to normal following stopping PPI or H2RA drugs. A study by Festen et al. showed that serum gastrin concentrations fell to pre-treatment concentrations 1 week following cessation of omeprazole.[56]

The clinical concern, however, is whether it is safe to stop PPI drugs to measure fasting serum gastrin concentrations, when there is a possibility of underlying ZES and thus a risk of precipitating complicated peptic ulcer disease. If the fasting serum gastrin concentration has to be measured in patients strongly suspected of having underlying ZES, then it has been proposed that PPI drugs should be stopped 1 week prior to the test, switching to an oral H2RA until 30 h prior to the test and then an intravenous continuous H2RA infusion until 12 h prior to measuring fasting serum gastrin concentration.[57] Other authors have suggested stopping PPIs 3 weeks and H2RAs 1 week prior to measuring serum gastrin concentrations.[58] The ENETS (European Neuroendocrine Tumour Society) Consensus Guidelines published in 2006, advise stopping PPIs at least a week prior to measuring fasting serum gastrin concentrations (with H2RA cover) in patients with suspected ZES. They reported that in people with ZES, the symptoms and clinical signs are usually not effectively suppressed by H2RA drugs; hence, these drugs are less of a confounding factor when measuring serum gastrin concentrations.[59]

With the available evidence, we therefore usually advocate stopping PPI and H2RA medications at least 1 week prior to measuring fasting serum gastrin concentrations. If there is a very strong suspicion of underlying ZES, then PPIs may be substituted by a H2RA drug and fasting serum gastrin concentrations should be measured after withholding the H2RA for 12 h. An alternative approach if ZES is very strongly suspected and a clinician is reluctant to stop PPI medication is to perform imaging studies such as CT scan, EUS and/or 111In-octreotide scan (somatostatin receptor scintigraphy scan) to evaluate the possible presence of gastrinoma prior to stopping PPI therapy. However, as discussed above, such imaging studies are sometimes negative, particularly when gastrinomas are small.

Helicobacter pylori Infection

Helicobacter pylori infection can also cause modest elevations in fasting serum gastrin concentrations. There are two potential mechanisms (Figure 2). In antral predominant H. pylori induced gastritis, there is inhibition of somatostatin release, leading to hypergastrinaemia, a subsequent increase in acid secretion and possibly duodenal ulcer formation. In contrast, in H. pylori induced chronic atrophic corpus gastritis, hypochlorhydria induces an appropriate G cell hyperplasia and thus hypergastrinaemia.[60] Infection usually results in an approximately two-fold increase in basal serum gastrin concentration and up to a six-fold increase following meal or bombesin (GRP) stimulation.[61,62]

Figure 2.

Mechanisms of induction of hypergastrinaemia in (a) antral predominant Helicobacter pylori infection and (b) H. pylori associated chronic atrophic gastritis.

Wagner et al. showed that patients with active gastritis secondary to H. pylori infection have higher fasting serum gastrin concentrations and that the degree of hypergastrinaemia correlated with the severity of mucosal inflammation.[63] In antral-predominant infection (in the absence of gastric atrophy), H. pylori infection is also associated with a reduction in serum somatostatin concentration, which results in unopposed gastrin secretion.[64] Somatostatin normally inhibits the synthesis and secretion of gastrin. Studies have shown that some of this normal inhibitory effect of somatostatin on gastric acid secretion is lost in the presence of Helicobacter infection,[10] but is restored upon eradication of this organism.[65] Queiroz et al. also demonstrated an increase in antral somatostatin concentration and an increase in antral D-cell density following eradication of H. pylori.[66] Various mechanisms have been proposed by which H. pylori influences somatostatin concentrations. These include effects of luminal ammonia produced by H. pylori,[67] effects of inflammatory cytokines induced by H. pylori infection[68] and reduction in the number of somatostatin D cells.[65,69,70,71,72]

Ohkusa et al. reported normalization of serum gastrin concentrations 12-15 months post-eradication of H. pylori.[73] In a prospective study, Chen et al. also observed a gradual decrease in serum gastrin concentrations to within the normal range 6 months after H. pylori eradication therapy. Recurrence of H. pylori infection was, however, associated with a further rise in serum gastrin concentration.[74] Similar reductions in serum gastrin concentrations 6 months following H. pylori eradication therapy have also been reported in at least two other studies.[75,76]

Helicobacter pylori infection may therefore contribute to mild hypergastrinaemia and it would therefore be considered reasonable to eradicate this infection and to repeat measurement of the fasting serum gastrin concentration 6 months later. If the concentration is persistently elevated and there is no histological evidence of gastric atrophy, other causes of hypergastrinaemia should be considered.

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