WIENER KLINISCHEWOCHENSCHRIFTThe Middle European Journalof Medicine

Printed in Austria

Wien Klin Wochenschr (2007) 119/19–20: 564–569DOI 10.1007/s00508-007-0878-0© Springer-Verlag 2007

Diagnose und Differentialdiagnose der Hypergastrinämie

Zusammenfassung. Die häufigste Ursache für einen erhöhten Gastrinspiegel beim Menschen sind das Zollin-ger-Ellison Syndrom mit autonomer Gastrinüberproduk-tion durch einen Tumor und die reaktive Hypergastrin-ämie im Rahen einer chronisch atrophen Autoimmun- (Typ A) Gastritis. Die Achlorhydrie bewirkt eine vermehr-te Gastrinausschüttung durch die antralen G-Zellen.

Die Entitäten unterscheiden sich durch den pH Wert der Magensäure. Dieser ist < 2 bei Vorliegen eines Zol-linger-Ellison Syndroms und neutral bei der Typ A Gas-tritis.

Die Behandlung mit Protonen Pumpen Inhibitoren, eine Magenausgangsstenose, eine Vagotomie, chro-nische Niereninsuffizienz oder ein Kurzdarmsyndrom können mit einer milden Hypergastrinämie ohne klinische Relevanz einhergehen.

Summary. The most frequent conditions of hyper-gastrinemia in man are the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the tumour cell and reactive hypergastrinemia in type A autoimmune chronic atrophic gastritis with achlorhydria causing un-restrained gastrin release from the gastrin-producing antral G-cells. Both entities differ with respect to the pH in the gastric fluid, which is < 2 in patients with Zollinger-Ellison syndrome and neutral in type A gastritis. Other conditions with moderate hypergastrinemia as treatment with proton pump inhibitors, gastric outlet obstruction, previous vagotomy, chronic renal failure or short bowel syndrome are of minor clinical importance.

Key words: Hypergastrinemia, Zollinger-Ellison syn-drome, chronic atrophic gastritis, type A gastritis.

Introduction

Circulating serum gastrin can arise from two sources: a) antral gastrin-producing G-cells and b) gastrin-produc-ing tumor cells. Gastrin-producing G-cells are situated in the intermediate third of antral glands and localized along their basal membrane. The activity of antral G-cells is contolled by somatostatin-producing D-cells which are situated in intimate vicinity to the G-cells [1]. The key experiment with infusion of an antiserum to somatostatin

producing a strong increase of gastrin indicates a close functional interrelationship between these two cells [2]. Figure 1 summarizes the regulators of antral G- and D-cells [3, 4]. The presence of acid and food in the stom-ach are the most important regulators. Acid stimulates antral D-cells. In a paracrine fashion somatostatin reach-es the neighbouring G-cells and inhibits the release of gastrin. On the other side, neutral environment as present in achlorhydria due to type A chronic-atrophic gastritis or in case of strong acid inhibition after intake of proton pump inhibitors decreases somatostatin release from the antral D-cells. Food stimulates the release of gastrin by direct activation of the antral G-cells and by inhibition of somatostatin release from D-cells. Also H. pylori inter-acts with antral G- and D-cells. Mediators from H. py-lori inhibit D-cells and contribute to increased basal and postprandial serum gastrin levels in H. pylori infected individuals [5].

Hypergastrinemia in man

Figures 2 and 3 summarize conditions with hyper-gastrinemia in man. Figure 3 offers, in addition, the phys-iological and pathophysiological background causing hy-pergastrinaemic states. There are two conditions with very high serum gastrin levels: a) the Zollinger-Ellison syndrome with autonomous gastrin hypersecretion by the gastrinoma tumour cells and b) type A gastritis with achlorhydria due to autoimmune atrophic gastritis of the fundic mucosa but normal architecture of the antral mu-cosa leading to a defect feedback inhibition of gastrin from the antral G-cells.

Zollinger-Ellison syndrome

The symptoms of patients with either a duodenal or pancreatic functionally active gastrin-producing tumour are the consequences of gastric acid hypersecretion sec-ondary to the secretion of gastrin by the tumour. Gastric acid hypersecretion induces severe acid related disorders as GERD, abdominal pain due to peptic ulcer disease and watery diarrhea. Increased fundic mucosal thickness, in-creased parietal cell mass, prominent gastric folds and proliferation of gastric enterochromaffin-like (ECL) cells result from the trophic effect of chronic hypergastrin-emia. In contrast to patients with type A chronic atrophic

Diagnosis and differential diagnosis of hypergastrinemia

Rudolf Arnold

Klinik für Innere Medizin, Schwerpunkt Gastroenterologie und Endokrinologie, Klinikum Giessen-Marburg, Standort Marburg, Philipps Universität, Marburg, Germany

565Arnold, Diagnosis and differential diagnosis of hypergastrinemia

gastritis and similarly elevated serum gastrin levels al-most all patients with Zollinger-Ellison syndrome present with marked gastric acid hypersecretion with a basal acid output (BAO) > 15 mEq/h and a luminal pH at endoscopy < 2. Fasting serum gastrin is > 5-times normal and in most patients > 500 pg/ml [6, 7]. In a recent NIH report on 235 patients, of whom 205 had no prior gastric surgery and 30 had prior gastric acid-reducing surgery BAO varied from 1.6 to 118 mEq/hr in patients without previous gas-tric-reducing surgery and from 5.9 to 102.9 mEq/hr in patients with previous gastric surgery [7]. In patients without previous gastric acid-reducing surgery and spo-radic disease BAO exceeded values of 18.6 mEq/hr in 90% and of 6.3 mEq/hr in 95% of patients. The respective values in patients with previous gastric acid-reducing sur-gery were 8.2 and 6 mEq/hr.

The pH of basal gastric acid secretion varied in this study from 0.83 to 1.99 in patients with previous gastric surgery and from 0.32 to 2.40 in patients without previous gastric surgery. 90%, 95% and 98% of patients without previous gastric acid-reducing surgery had a pH value of ≤ 1.42, ≤ 1.58 and ≤ 1.73, respectively. There were only slight differences between patients with or without previ-ous gastric acid-reducing surgery [7].

Since the interpretation of an elevated serum gastrin value is mainly based on the presence or absence or gas-tric acidity and since estimation of BAO is only possible in few specialized clinical settings, the demonstration of a pH < 2 in the gastric fluid and high serum gastrin levels support the diagnosis of a Zollinger-Ellison syndrome.

A fasting serum gastrin level of 1000 pg/ml and greater in the presence of a pH < 2 is virtually diagnostic of Zollinger-Ellison syndrome. However, approximately 68% of patients with Zollinger-Ellison syndrome have only a moderate elevation of serum gastrin between 100 and 1000 pg/ml as shown in Fig. 4 [8]. Similarly moder-ately elevated serum gastrin levels can also be present in conditions listed in Figs. 2 and 3 as H. pylori infection, retained gastric antrum after gastrectomy, in patients after massive small bowel resection or secondary to gastric

outlet obstruction and in some patients treated with proton pump inhibitors. To differ between these entities with serum gastrin levels between 100 and 1000 pg/ml a se-cretin test can be of diagnostic significance as demon-strated in Fig. 5. The sensitivity of the secretin test in patients with Zollinger-Ellison syndrome and fasting se-rum gastrin levels below 1000 pg/ml was 93% using the criterion of an increase of at least 110 pg/ml (Fig. 5) and 85% for an increase of 200 pg/ml [8]. In contrast, simi-larly elevated serum gastrin levels from patients with re-tained gastric antrum after gastrectomy (“excluded an-trum”), antral G-cell hyperfunction (Fig. 5) or type A gastritis decrease after secretin. In the literature several additional tests have been described based on the abilitiy of stimulants as calcium, theophyllin, bombesin, glucagon and other compounds to stimulate the release of tumour gastrin but not the release of gastrin from normal antral G-cells. Of these tests only the calcium infusion test has shown to be of practical value. However its sensitivity is lower than that of the secretin test and an increase of 395 pg/ml from basal has been found to be diagnostic [8]. The calcium infusion test should be used if the secretin test is negative and the diagnosis of a Zollinger-Ellison syn-drome is still uncertain.

acidSmallbowelfactor

Fundicfactor

fasting BombesinPresenceof food

NeutralpH

D-cell

G-cell

H. pylori

?

Fig. 1. Regulation of the densities of antral G- and D-cells

Gastric outletobstruction

Antrale G-cell hyper-function (H-pylori)

Zollinger-Ellison syndrom

Typ-A-gastritis Vagotomy Proton pump

inhibitors

Renal insufficiency

Short bowel syndrome

Fig. 2. Hypergastrinemia in different clinical states

566 Arnold, Diagnosis and differential diagnosis of hypergastrinemia

1. Autonomic gastrin secretion despite intact feedbackof acid and gastrin in Zollinger-Ellison syndrome

2. No feedback inhibition of the antral G-cells by acid• Typ A-Gastritis• Vagotomy• Proton pump inhibitors• excluded antrum after B II

3. Defective gastrin metabolism• renal insufficiency• short bowel syndrome

4. H. pylori infection

Gastrin

-

-

-

Fig. 3. Hypergastrinemic states according to underlying pathophysiological events

Fig. 4. Basal serum gastrin levels in different clinical states related to peptic ulcer disease

Fig. 5. Response of serum gastrin to i.v. secretin in a patient with Zollinger-Ellison syndrome, antral G-cell hyperfunction, excluded antrum and in patients with duodenal ulcer disease. Notice that the patients with gastrinoma, antral G-cell hyper-function and excluded antrum had basal serum gastrin levels in the same magnitude. Only the patient with Zollinger-Ellison syndrome responded to secretin with an exaggerated increase

of serum gastrin

Antral G-cell hyperfunction

Since the wide distribution of proton pump inhibitors antral G-cell hyperfunction is a “historical disease”. Sev-eral studies indicate that antral G-cell hyperfunction is related to an infection with H. pylori but only few in-fected patients develop the syndrome of “antral G-cell

hyperfunction” with massive gastric acid hypersecretion, moderate to severe hypergastrinemia, exaggerated gastrin release after food (Fig. 6) and normalisation of gastric acid hypersecretion and hypergastrinemia after antrecto-my [9–11] or H. pylori eradication [12]. The demonstra-tion that eradication of H. pylori infection normalizes hypergastrinemia, gastric acid hypersecretion and ulcer

567Arnold, Diagnosis and differential diagnosis of hypergastrinemia

disease proves the assumption that antral G-cell hyper-function is the consequence of H. pylori infection. It has been demonstrated that antral somatostatin concentration is significantly decreased in these patients explaining the increased gastrin secretion from antral G-cells [5]. It is unknown why this phenomenon is present only in few and not in all infected patients. Since H. pylori eradication is the treatment of choice in peptic ulcer patients this syn-drome is now adequately treated before the diagnosis of antral G-cell hyperfunction has been ascertained.

Excluded antrum

This is also a “historical disease”. Retained gastric antrum after Billroth II gastrectomy was occasionally seen in the area where surgery was the key therapeutic principle in peptic ulcer disease, i.e. before the introduction of H2-receptor antagonists and proton pump inhibitors. At that time Billroth I or II gastric resection was the gold standard

in peptic ulcer treatment. Part of the prepyloric antrum was left on the stump of duodenal bulb and disconnected from the acid flow. This gave rise to marked hypergastrin-emia and to gastric acid hypersecretion and its sequelae as GERD and peptic ulcer disease [13, 14].

Achlorhydria in Type A Gastritis and reduced gastric acid secretion due to vagotomy and acid

inhibiting drugs

Type A chronic atrophic gastritis which can or cannot be associated with pernicious anaemia is the classical example of achlorhydria in man. It results from an auto-immune mediated loss of fundic parietal cells whereas the antral mucosa remains intact. The autoimmune process in the fundus progresses to severe and life-long persisting atrophic gastritis. The consequence of achlorhydria is an increase of antral G-cell and a decrease of antral D-cell density within the intact antrum and hypergastrinemia

Fig. 6. Serum gastrin levels in response to a test meal in patients with antral G-cell hyperfunction. Notice the exaggerated increase of serum gastrin compared to patients with peptic ulcer disease before and after selective proximal vagotomy

568 Arnold, Diagnosis and differential diagnosis of hypergastrinemia

with serum gastrin levels similar to those observed in Zollinger-Ellison syndrome. Both types of hypergastrin-emia can be distinguished by a) the gastric pH which is < 2 in Zollinger-Ellison syndrome and > 5 in type A gas-tritis, b) the presence of chronic atrophic gastritis in the gastric corpus and of a normal mucosa in the antrum of patients with type A gastritis, whereas the gastric mucosa in the antral and fundic part of the stomach of patients with Zollinger-Ellison syndrome is intact and c) the lack of symptoms related to gastric acid hypersecretion in patients with type A gastritis.

As shown in Fig. 4 for patients with previous selective proximal vagotomy serum gastrin is modestly elevated in vagotomized patients due to several mechanisms: increase in luminal pH as a consequence of vagotomy, chronic antral distention due to a functional impairment of gastric emptying and a vagally mediated gastrin cell inhibitor in the fundus destroyed by the surgical procedure. The hy-pergastrinemia after vagotomy is an epiphenomeon with-out any clinical significance.

Of more clinical importance is the modest increase of serum gastrin in patients under long-term treatment with acid-lowering compounds. This increase is the direct consequence of inhibition of gastric acid secretion by the compounds, mostly proton pump inhibitors (PPI). All patients under long-term PPI therapy develop hypergas-trinemia [15–19]. Hypergastrinemia during long-term PPI therapy is moderate and median increases of 100 to 155% has been described. However, in some individuals with elevated serum gastrin levels before start of PPI therapy serum gastrin can increase up to 1000 pg/ml and more. The reasons are not entirely clear. Preexisting H. pylori infection with corpus-dominant atrophic gastritis could explain this exaggerated gastrin increase. It was sug-gested that the hypergastrinemia could be an important triggering mechanism for the development of fundic ECL-cell abnormalities as shown in Figs. 8–10. Gastric carcinoids occur in man only in patients with type A

Gastric Carcinoid Development

Profound acid inhibition

Decrease in antral D-cellsIncrease in antral G-cells

Hypergastrinaemia

ECL-cell hyperplasiadiffuse, micronodular)

ECL-cell dysplasia

ECL-cell carcinoid

Fig 7. Mechanism of carcinoid development in type A-gas-tritis

Fig. 8. Sporadic carcinoid of the gastric fundus in type A gastritis

Fig. 9. Linear ECL-cell hyperplasia in type A-gastritis

Fig. 10. Linear and micronodular ECL-cell hyperplasia in type A-gastritis

569Arnold, Diagnosis and differential diagnosis of hypergastrinemia

gastritis by a mechanism shown in Fig. 7 and in the fun-dic mucosa of patients with Zollinger-Ellison syndrome as part of the Multiple Endocrine Neoplasia-I (MEN-I) syndrome but not in patients treated with PPIs. There a numerous studies on this subject published in recent years disproving any evidence for the assumption of carcinoid formation during PPI treatment. PPI treatment as cur-rently used in patients with chronic peptic disorders as GERD, Helicobacter pylori negative peptic ulcer disease or as prohylaxis in patients treated with NSAIDs is safe and serum gastrin should not be monitored if the peptic disorder is controlled by a standard dosis of the PPI. Only if higher doses are necessary, a Zollinger-Ellison syn-drome should be excluded as outlined above.

Summary

1) Hypergastrinemia is of clinical and diagnostic im-portance only in patients with Zollinger-Ellison syndrome. In patients with relapsing ulcer disease despite Helico-bacter pylori eradication or severe GERD despite long-term treatment with PPI in normal doses serum gastrin should be measured. In case of moderately to very high serum gastrin levels either BAO or – more comfortable – gastric pH should be monitored. Is the pH < 2 the pres-ence of a Zollinger-Ellison syndrome is very likely. Is the pH > 2 and if the patient is under long-term treatment with PPIs, this medication should be discontinued for at least 1 week and gastric pH again monitored. Is the pH < 2 consider Zollinger-Ellison syndrome. In case of a pH > 3 a Zollinger-Ellison syndrome is exluded.

2) Measurement of serum gastrin can be helpful in patients with histologically confirmed type A gastritis to confirm the diagnosis by demonstrating hypergastrin-emia. This includes also patients with ECL-cell abnor-malities described by the pathologist as shown in Fig. 6.

3) No indication for measurement of serum gastrin is Helicobacter pylori infection, unexplained upper gastro-intestinal complaints and treatment with any of the avail-able acid lowering drugs including PPIs since all patients treated with these compounds have elevated serum gastrin which is without any significance.

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Correspondence: Prof. Dr. Rudolf Arnold, Wittelsbacher-straße 6, 80469 München, Germany, E-mail: arnoldr@mailer.uni-marburg.de