Can a patient have a normal chromogranin A (CgA) level with an abnormal serum gastrin level?

Yes, Normal Chromogranin A with Elevated Gastrin is Common

A patient can absolutely have a normal chromogranin A (CgA) level despite having an abnormal serum gastrin level, and this occurs frequently in clinical practice. In fact, approximately 11 out of 40 gastrinoma patients (27.5%) had normal CgA concentrations despite elevated gastrin levels in one study 1.

Why This Discordance Occurs

Different Sources of Secretion

• Gastrin originates from the gastrinoma tumor itself in patients with Zollinger-Ellison syndrome, making it a direct marker of the tumor 2
• CgA can originate from either the tumor OR from enterochromaffin-like (ECL) cell hyperplasia in the gastric mucosa secondary to hypergastrinemia 2, 3
• In gastrinoma patients, CgA elevation correlates strongly with serum gastrin levels (r=0.82) but not with ECL cell proliferation, indicating CgA is released from the gastrinoma itself rather than from gastric ECL cells 2

CgA is Not a Reliable Marker for Gastrinomas

• CgA was elevated in only 60% of neuroendocrine tumors overall, meaning 40% have normal levels despite active disease 4, 5
• In gastrinoma specifically, CgA measurements are not valid for diagnosis or control of these tumors 1
• CgA can be normal or near-normal (<75 ng/mL) even in patients with very high serum gastrin levels and established gastric carcinoids 2

Clinical Implications for Diagnosis

Gastrin is the Primary Diagnostic Test

• Measure fasting serum gastrin after discontinuing proton pump inhibitors for at least 1 week 6, 4, 7
• A combination of fasting serum gastrin >10 times elevated AND gastric pH <2 is diagnostic of gastrinoma 6
• Most patients with elevated gastrin do NOT have gastrinoma but rather have achlorhydria or are receiving proton pump inhibitors 6

CgA Should Not Replace Gastrin Testing

• CgA cannot identify patients with advanced ECL cell changes with high sensitivity/specificity and therefore cannot replace routine gastric biopsies or gastrin measurements 3
• The gastrin/progastrin parameters have high diagnostic value, whereas CgA measurements do not add diagnostic value beyond gastrin testing in gastrinoma patients 1

Important Confounders to Consider

False Elevation of CgA (Without Tumor)

• Proton pump inhibitors cause spurious CgA elevation through increased gastrin secretion and subsequent ECL cell stimulation 6, 4, 8
• Renal failure, liver failure, hypertension, and chronic gastritis all cause false CgA elevation 6, 4, 5

False Elevation of Gastrin (Without Gastrinoma)

• Proton pump inhibitors increase serum gastrin 1.3 to 3.6-fold and should be stopped 10 days to 2 weeks before testing 7, 8
• Achlorhydria from atrophic gastritis causes hypergastrinemia 6, 9
• H. pylori infection and atrophic gastritis are prevalent conditions leading to hypergastrinemia 9

Practical Diagnostic Algorithm

When evaluating suspected gastrinoma:

1. Stop proton pump inhibitors for 1-2 weeks before any biochemical testing 6, 7
2. Measure fasting serum gastrin and gastric pH as the primary diagnostic tests 6
3. Obtain multiphasic CT or MRI for tumor localization 6, 4
4. Consider CgA only as a category 3 (optional) test that may help with prognosis if elevated, but do not rely on it for diagnosis 6, 4
5. If CgA is elevated, determine gastrin levels to distinguish neuroendocrine tumor from hypergastrinemia-induced ECL hyperplasia 9

Key Pitfall to Avoid

Do not exclude gastrinoma based on a normal CgA level. The absence of CgA elevation does not rule out gastrinoma or other neuroendocrine tumors, as CgA is elevated in only 60% of cases 4, 5. Always rely on gastrin levels and imaging for gastrinoma diagnosis, not CgA 6, 1.