gastrin-17 and Zollinger-Ellison-Syndrome

Gastrin measurements are performed primarily for the diagnosis of gastrin-producing tumors, gastrinomas, which cause the Zollinger-Ellison syndrome (ZES). Gastrin circulates as several bioactive peptides, however, and the peptide pattern in gastrinoma patients often deviates from normal. Therefore, it is necessary to measure all forms of gastrin.. Only immunoassays are useful for measurement of gastrin in plasma. The original assays were RIAs developed in research laboratories that used antibodies directed against the C terminus of gastrin peptides. Because the C-terminal tetrapeptide amide sequence constitutes the active site of gastrin peptides, these assays were well suited for gastrinoma diagnosis. More recently, however, most clinical chemistry laboratories have switched to commercial kits. Because of recent cases of kit-measured normogastrinemia in patients with ZES symptoms, the diagnostic sensitivity and analytical specificity of the available kits have been examined. The results show that gastrin kits frequently measure falsely low concentrations because they measure only a single gastrin form. Falsely high concentrations were also encountered, owing to overreactivity with O-sulfated gastrins or plasma proteins. Thus, more than half of the gastrin kits on the market are unsuited for diagnostics.. Gastrinomas are neuroendocrine tumors, some of which become malignant. A delay in diagnosis leads to fulminant ZES, with major, even lethal, complications. Consequently, it is necessary that the diagnostic sensitivity of gastrin kits be adequate. This diagnostic sensitivity requires antibodies that bind the C-terminal epitope of bioactive gastrins without the influence of O-sulfation.

Topics: Amino Acid Sequence; Antibody Specificity; Biomarkers, Tumor; Gastrinoma; Gastrins; Humans; Immunoassay; Molecular Sequence Data; Reagent Kits, Diagnostic; Sensitivity and Specificity; Zollinger-Ellison Syndrome

Forty-six patients with the gastrinoma syndrome were divided into 2 categories: 1) benign sporadic gastrinoma (n = 30), and 2) gastrinoma with metastases to liver (n = 16). Thirteen of the 46 patients had multiple endocrine neoplasia type I syndrome. Serum gastrin levels in patients fasted overnight were determined by RIA using antisera directed toward the NH2- and COOH-terminals of heptadecapeptide gastrin (G17) and the NH2-terminus of the triacontatetrapeptide (G34). These results were compared with findings in 50 normal subjects. In the normal subjects, the mean COOH-terminal gastrin-17 level was higher [65 +/- 8 (+/- SEM) pg/ml] than the NH2-terminal gastrin-17 level (11 +/- 0.2 pg/ml) and lower than the NH2-terminal gastrin-34 level (134 +/- 20 pg/ml). The levels of NH2-terminal gastrin-17 were higher in patients with metastatic disease than in those with benign gastrinoma, whereas the COOH-terminal gastrin-17 and the NH2-terminal gastrin-34 levels were similarly high in both groups. The mean ratio of NH2-terminal gastrin-17 to COOH-terminal gastrin-17 was less than 1 in normal subjects (0.22 +/- 0.02) and benign gastrinoma patients (0.2 +/- 0.04), and it was 2.2 +/- 0.41 in the patients with metastatic gastrinoma. An NH2 to COOH gastrin-17 ratio greater than 1 was found in 13 of 16 patients with metastatic gastrinoma, but in none of the patients with benign gastrinoma or normal subjects. Similar results were found in multiple endocrine neoplasia type I patients with benign and metastatic disease. A high NH2 to COOH gastrin-17 ratio is suggestive of metastatic gastrinoma. In 4 patients with metastatic gastrinoma, the NH2 to COOH gastrin-17 ratio fell in parallel with the response to chemotherapy.

Topics: Chromatography, Gel; Gastrins; Humans; Liver Neoplasms; Multiple Endocrine Neoplasia; Protein Precursors; Radioimmunoassay; Zollinger-Ellison Syndrome

Gastrin- 17 (G-17) and gastrin-34-like immunoreactivities of human gastrinoma cells were investigated at light and electron microscope level using N-terminally directed antisera. The procedure includes (a) the 24 hr/immunoperoxidase staining of Bouin-fixed paraffin embedded tissues, (b) the immunoelectron microscopic labelling of aldehyde-fixed Epon-embedded tissues according to the immunogold technique. On light microscopy, a variable number of tumor cells stained for G-34. In contrast, G-17 immunoreactivity was very low or undetectable in the tumor material, although it was easily detected in endocrine cells of similarly processed human pyloric mucosa. On electron microscopy, most of the tumor cell granules belonging to the round compact or dense-cored type exhibited a variable labelling for G-34, whereas the vacuolar/floccular type remained unlabelled. In contrast, the labelling for G-17 occurred over most of the tumor cell granules, whether compact or floccular. Dense granules of varying size and shape, previously shown to store C-terminal gastrin immunoreactivity, were only faintly labelled by the two antisera. When compared to the labelling pattern of human pyloric G-cells, the predominance of round dense granules with G-34 and G-17 immunoreactivity in gastrinoma cells suggests an incomplete or defective post-translational processing of the precursor peptide.

Topics: Colloids; Gastrins; Gold; Humans; Immune Sera; Immunoassay; Immunoglobulin G; Microscopy; Microscopy, Electron; Protein Precursors; Zollinger-Ellison Syndrome

Topics: Gastrins; Humans; Protein Precursors; Radioimmunoassay; Reagent Kits, Diagnostic; Zollinger-Ellison Syndrome

A radioimmunochemical procedure which distinguishes sulfated from non-sulfated gastrins has been developed. Two antisera raised against synthetic non-sulfated human hexadecapeptide gastrin were used. No. 2604 binds sulfated and non-sulfated gastrins with equimolar potency, whereas No. 2605 reacts poorly with sulfated gastrin (ID50 for non-sulfated gastrin: ID50 for sulfated gastrin = 0.06). Both antisera bind gastrins of different molecular length with equimolar potency using monoiodinated human gastrin-17 as tracer. The method was validated by fractionating gastrins in serum and in tissue extracts, and by recovery experiments. We found that Component I of gastrin--like the smaller gastrin components--was present in both, sulfated and non-sulfated form. In serum from normal fasting subjects the concentration of non-sulfated gastrin was 12.5 +/- 0.8 pmol/l (mean +/- SEM) with a total range of 0-44 pmol/l and the corresponding values for sulfated gastrin were 7.5 +/- 0.5 pmol/l (range 0-20 pmol/l). Sulfated gastrin accounted for more than half of the gastrins in only 21% of normal subjects. There was a parallel rise and fall in sulfated and non-sulfated gastrins after a meal and after stimulation with adrenaline.

Topics: Animals; Eating; Epinephrine; Gastrins; Humans; Pyloric Antrum; Radioimmunoassay; Sulfuric Acids; Swine; Zollinger-Ellison Syndrome

Topics: Chromatography, Ion Exchange; Gastrins; Humans; Liver Neoplasms; Prognosis; Radioimmunoassay; Zollinger-Ellison Syndrome