Seven of 12 commercially available kits for measuring plasma gastrin levels yielded inaccurate results, putting patients with Zollinger-Ellison syndrome at risk for severe – even lethal – complications, Dr. Jens F. Rehfeld and his colleagues reported in the May issue of Gastroenterology.

Zollinger-Ellison syndrome, which is caused by excessive release of gastrin from endocrine tumors called gastrinomas, is characterized by hypersecretion of gastric acid; aggressive peptic disease in the upper small intestine, with ulceration and often perforation; and severe diarrhea. The diagnosis is usually established by the detection of elevated gastrin concentrations in plasma, often via 1 of the 12 commercially available immunoassay kits.

Dr. Rehfeld of the University of Copenhagen Rigshospitalet and his associates assessed the diagnostic reliability of these kits after treating two patients who developed severe complications when the assays gave false-negative results for their plasma gastrin levels.

The first patient, a 49-year-old man who presented with diarrhea and profuse vomiting, required ICU care for hypovolemic shock and acute renal failure. Zollinger-Ellison syndrome was suspected but discounted once an assay showed normal levels of plasma gastrin. When empiric IV pantoprazole was stopped, the patient resumed vomiting acidic fluid, which caused multiple esophageal strictures. These prevented him from eating for weeks, and required that he undergo forced serial dilations of the esophagus for a period of years.

A remeasurement of his gastrin levels in another plasma sample using the same assay again yielded normal results, but a test of the new sample with a different assay showed elevated gastrin. With Zollinger-Ellison syndrome again suspected, the patient underwent exploratory laparotomy, which revealed hepatic neuroendocrine tumor metastases but no primary tumor.

Progression of the metastases was stabilized with chemoembolization and octreotide. The patient continues to take esomeprazole to control acid secretion 4 years later, and requires esophageal dilations every 2-3 months for recurrent strictures.

The second patient was a 51-year-old man who presented with severe abdominal pain, vomiting, diarrhea, and dehydration for 6 months with a 15-kg weight loss. He improved rapidly with IV pantoprazole and fluids. An assay showed only a slight elevation in plasma gastrin, which was attributed to the patient’s long-term use of proton pump inhibitors and his dehydration.

But the patient relapsed after IV treatment concluded, and he experienced repeated episodes of dehydration as well as severe ulcerations with microperforation of the distal duodenum. A second plasma gastrin assay again gave normal results, but a test of basal gastric acid output showed hypersecretion even while he was on pantoprazole therapy. Laparotomy revealed lymph node metastases of a neuroendocrine tumor, but no primary tumor was identified. The patient continues to take esomeprazole to control acid secretion 6 years later.

After treating these cases, Dr. Rehfeld and his colleagues tested plasma samples from 40 patients with known or suspected Zollinger-Ellison syndrome, using the 12 assay kits they identified in an Internet search (7 radioimmunoassays and 5 ELISAs). They compared the results with those of a very accurate, in-house radioimmunoassay–based reference test.

Only one kit (Eurodiagnostica) gave accurate results for 100% of the tests. Two kits (MP Biomed and Siemens RIA) gave accurate results for 95%, and two (DRG and Siemens Immulite) did so for 90%. The remaining kits performed poorly: Two kits (Peninsula and Phoenix EIA) gave accurate results for only 75% of the tests, two (DiaSorin and Biohit) for only 60%, one (US Biological) for only 55%, and one (Phoenix RIA) for only 40%. The final kit (Correlate) gave accurate results for 100% of patients who had elevated gastrin levels but also gave false-positive results in eight of eight patients who actually had normal gastrin levels.

The investigators further discovered that failures of these assays resulted from their inclusion of reactive antibodies "that do not appropriately recognize the molecular forms of gastrin secreted by gastrinomas."

Gastrin circulates in multiple molecular forms, with peptide patterns that vary considerably, "not only between normal subjects and Zollinger-Ellison patients as such, but also among the individual gastrinoma patients," they explained. In many of the assays, the antibodies simply failed to recognize and bind to some of these forms of gastrin.

Two assays that gave false-positive results were found to be sensitive to "unspecific plasma effects" or to overreact with sulfated gastrins. "False ‘high’ concentrations are a cause of anxiety, and the patients have to undergo unnecessary and costly investigations. At its extreme, they can lead to unnecessary surgery and inappropriate life-long treatment," Dr. Rehfeld and his associates said.

The study findings also implicate assay kits that are used to detect other neuroendocrine tumors, which release peptide hormones that – like gastrin – circulate in different molecular forms. "An obvious question is, therefore, whether the immunoassay kits used for the other neuroendocrine tumors have the necessary diagnostic sensitivity and specificity," they noted.

This study did not have any grant support, and no conflicts of interest were reported.

Zollinger-Ellison Syndrome: Plasma Gastrin Measurement Kits Often Inaccurate