Measurements of chromogranin B can serve as a complement to chromogranin A

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Abstract

Objective

CgA has been shown to be an excellent marker for neuroendocrine tumours. However, there are two major drawbacks with CgA measurements; elevated levels are common in patients with decreased renal function and in patients on treatment with proton pump inhibitors. These problems are not seen with CgB measurements. We have recently presented the development of 13 region-specific radioimmunoassays for measurements of CgB. A region-specific assay was identified, which measured higher concentrations of CgB than the other assays and seemed to be very useful as a marker for neuroendocrine tumours. The aim of the present study was therefore to further explore the diagnostic potential of this assay in the clinical management of patients with neuroendocrine tumours.

Methods

Measurements of CgB with two methods were compared with CgA in plasma samples from patients investigated for neuroendocrine tumours (N = 86), patients with decreased renal function (N = 35) and patients on treatment with proton pump inhibitors (N = 29).

Results

The diagnostic sensitivity for the new CgB assay was almost as good as that for CgA. Furthermore, with CgB measurements we could avoid the falsely elevated levels of CgA found in patients with decreased renal function and treatment with proton pump inhibitors.

Conclusions

We conclude that the new CgB assay can serve as a complement to CgA measurements as an important tumour marker for neuroendocrine tumours.

Introduction

Chromogranin B (CgB) is an acidic glycoprotein consisting of 657 amino acids and a molecular mass of about 70 kD, occurring in the secretory granules of neuroendocrine cells. In most neuroendocrine tissue, CgB co-exists together with chromogranin A (CgA). The primary structure of human CgB contains 15 pairs of basic amino acids, which are potential cleavage sites for specific endogenous proteases, but also other sites in the molecule can be subjected to cleavage. CgB-related peptides have been identified in both humans and animals and some of these have been shown to possess biological activity [1].

CgA is widely used as a marker for neuroendocrine tumours and commercial assays are available [2]. However, CgB is not used as a common circulating marker, probably due to excellent results with CgA and also due to the lack of commercial assays. In clinical practise, there are two major drawbacks of CgA measurements; elevated levels of CgA are common in patients with decreased renal function and in patients on treatment with proton pump inhibitors, although no neuroendocrine tumour is present [3], [4], [5], [6]. Other causes of non-tumour related increases of CgA are type A gastritis and heart failure [7], [8]. We have, since 1995, presented data on circulating CgB concentrations in several publications, using an in-house method, which shows that CgB can be used as a complement to CgA measurements since the above drawbacks not are present for CgB see for example [4], [9].

We have recently presented articles which describe the production of antibodies against several specific parts of the CgB molecule and also the development of 13 region-specific radioimmunoassays against these parts of the molecule [1], [10]. In one of the articles we identified a region-specific assay, which measured higher concentrations of CgB than the other assays and seemed to be more useful as a marker for neuroendocrine tumours [1]. The aim of this study was therefore to further explore the diagnostic potential of this assay in the clinical management of patients with neuroendocrine tumours.

Section snippets

Patients and blood samples

Patients were recruited consecutively during three months period at a national referral centre for neuroendocrine tumours. The patients represented a variety of diagnoses, from known neuroendocrine tumours on different treatment to new cases submitted for investigation. This patient group comprised 86 patients, where 58 patients had clinically manifest neuroendocrine tumours of various types, indicated by the presence of primary tumours or metastases that could be radiologically verified. Of

Reference ranges

The CgA and the CgB312-331 assays have been used for several years and have established reference intervals of < 4,0 and < 2.0 nmol/L respectively. From the 214 normal individuals a reference range was calculated for the CgB439-451 method. When calculation from the 2.5% and 97.5% percentiles was used, the reference interval became 0.52–1.69 nmol/L, with a median value of 0.95 nmo/L. When the reference interval was calculated from MV+ /  2SD the result was 0.31–1.71 nmol/L, with a mean of

Discussion

CgA is a well established marker for the diagnosis and follow up of treatment for neuroendocrine tumours and several studies have shown the value of these measurements [4], [9], [12], [13], [14], [15], [16]. In clinical practise however, there are two major drawbacks of CgA measurements; elevated levels of CgA are common in patients with decreased renal function [3], [4] and in patients on treatment with proton pump inhibitors [5], [6].

In an elderly population slightly or manifest decreased

Acknowledgements

This work was accorded grants from the Swedish Cancer Society, the Lions Cancer Foundation and the Selanders Foundation.

We are grateful for the excellent technical assistance from Ulla-Britta Jansson and Inger Olsson.

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