Chromogranins and/or secretogranins constitute a family of water-soluble acidic glycoproteins that are present in almost all endocrine, neuroendocrine and neuronal tissue. Antibodies against chromogranins have been widely used for immunohistochemical staining of endocrine tissue and tumours of neuroendocrine origin. Furthermore, measurements of circulating chromogranin A have been used as a reliable marker for neuroendocrine tumour growth. In this study, we describe the development of specific antibodies against chromogranin A, chromogranin B (secretogranin I), chromogranin C (secretogranin II) and pancreastatin. The antibodies were used for immunohistochemical staining of normal and neoplastic neuroendocrine tissue and development of reliable radioimmunoassays for chromogranin A, chromogranin B, chromogranin C and pancreastatin. In 44 patients with carcinoid tumours, 17 patients with sporadic endocrine pancreatic tumours and 11 patients with endocrine pancreatic tumours and the multiple endocrine neoplasia 1 syndrome, plasma measurements revealed elevated chromogranin A levels in 99%, elevated chromogranin B in 88%, elevated chromogranin C in 6% and elevated pancreastatin in 46% of the patients. Urinary measurements revealed elevated levels in 39%, 15%, 14% and 33% of the patients respectively. Gel permeation chromatography of plasma and urine showed that circulating chromogranin A, and immunoreactive fragments of chromogranin A, had a higher molecular weight distribution than the chromogranin A fragments excreted to the urine. Furthermore, it was noted that most of the patients excreting chromogranin A fragments to the urine had previously been treated with streptozotocin, a cytotoxic agent known to induce renal tubular dysfunction. The antibodies raised proved useful for immunohistochemical staining and visualised endocrine cells in pancreatic islets, adrenal medulla and the small intestine as well as in endocrine pancreatic tumours, pheochromocytoma and midgut carcinoid tumours. In conclusion, the antibodies raised were useful for both immunohistochemical staining of normal tissue and endocrine tumours as well as development of specific radioimmunoassays for plasma measurements of the different chromogranins. Furthermore, we show that plasma measurements of chromogranin A and B were superior to measurements of chromogranin C and pancreastatin and plasma measurements of the different chromogranins were more reliable as markers for tumour growth than the corresponding urine measurements.

A total of 80 individuals in 4 kindreds with multiple endocrine neoplasia type 1 (MEN 1) have been subjected to repeated biochemical screening during a 10-yr period with the principal aim being to analyze characteristics of the developing pancreatic lesion. Age at presentation of the MEN 1 trait averaged 18 yr in 7 previously unaffected individuals, and this effect of the screening procedure represented a lowering by almost 2 decades. Pancreatic endocrine involvement was recognized at a mean age of 25 yr and constituted the presenting lesion in a majority of the patients. A standardized meal test and basal values of serum pancreatic polypeptide, insulin, proinsulin, and gastrin were the most efficient markers for the pancreatic lesion and preceded signs of pancreatic tumors upon radiological examinations by a mean of 3.5 yr. A 75% penetrance of the islet cell disease and 90% for primary hyperparathyroidism within the affected individuals equalled the prevalences reported in autopsy studies. Two of the kindreds showed signs of intrafamilial homogeneity with respect to the profile of peptide excess (P less than 0.05) and considerable discrepancy in the malignant potential of the pancreatic lesions. The results of early detection and surgical intervention of the pancreatic tumors in MEN 1 suggested an impact on morbidity, while any effect on the mortality of these individuals remains to be clarified.

In a prospective study of 103 patients with carcinoid tumors consecutively referred for medical treatment, the most common sites of the primary tumors were the ileum (73%), bronchi (7%), and jejunum (4%). All patients had local metastases, and 96 (93%) also had liver metastases. The most common initial symptoms were diarrhea (32%), ileus (25%), and flush (23%). The overall frequency of diarrhea was 84% and of flush was 75%. Heart insufficiency caused by cardiac valve disease was seen in 33% of the patients. The carcinoid syndrome, including flush, diarrhea, and elevated urinary 5-hydroxyindole acetic acid (5-HIAA) concentrations, was manifested by 69 patients (67%), 64 of whom (93%) had carcinoid tumors of mid-gut origin. Elevated urinary 5-HIAA was found in 91 patients (88%), of which 89 displayed liver metastases. The plasma concentration of the tachykinin neuropeptide K (NPK) was elevated in 67 patients (66%), 63 of whom had tumors of the mid-gut region. Serum pancreatic polypeptide (PP) and human chorionic gonadotrophin alpha levels were elevated in 43% and 28% of the patients, respectively, and the highest levels were found in patients with metastatic bronchial carcinoid tumors. Thirty-nine of the 103 patients are now dead; 18 died of tumor progression, whereas 14 patients died of heart failure secondary to a carcinoid tricuspidal valve insufficiency. The estimated median survival from the time of histologic diagnosis was 14 years, and from the time of carcinoid syndrome was 8 years.

During long-term gastric acid inhibition, serum CgA levels reflect the presence and severity of fundic ECL cell hyperplasia. Serum CgA is therefore a useful screening test for gastric ECL cell proliferative changes within this context.