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© Borgis - Postępy Nauk Medycznych 12/2014, s. 847-851
*Piotr Glinicki, Wojciech Jeske
Chromogranina A (CgA): budowa, funkcja biologiczna, przedanalityczne, analityczne i kliniczne aspekty oznaczania jej we krwi
Chromogranin A (CgA): structure, biological function, pre-analytical, analytical, and clinical aspects of its measurement in blood
Department of Endocrinology, Centre of Postgraduate Medical Education, Bielański Hospital, Warszawa
Head of Department: prof. Wojciech Zgliczyński, MD, PhD
Streszczenie
Chromogranina A (CgA) jest głównym, niespecyficznym markerem guzów neuroendokrynnych (NET). Obecnie dostępnych jest kilka komercyjnych testów: RIA, IRMA, ELISA, CLIA, TRACE. Istnieje wiele czynników: in vivo, in vitro i współistniejących chorób, które mogą wpływać na stężenie CgA we krwi. Podwyższone stężenie CgA we krwi obserwujemy zwykle w: guzach neuroendokrynnych przewodu pokarmowego (GEP-NET), pheochromocytoma, neuroblastoma, zespołach MEN, guzach neuroendokrynnych oskrzeli, raku rdzeniastym tarczycy, raku drobnokomórkowym płuc oraz w innych rzadkich guzach NET. Pomiar stężenia CgA jest obecnie rutynowo stosowany w diagnostyce guzów GEP-NET, ale szczególnie jest on przydatny w monitorowaniu efektów leczenia. CgA może być dodatkowym badaniem w diagnostyce pheochromocytoma. U pacjentów z zespołem mnogich nowotworów endokrynnych (MEN) i u członków ich rodzin oznaczanie stężenia CgA może służyć ich monitorowaniu, aby jak najwcześniej wykryć pojawienie się w toku obserwacji guza neuroendokrynnego trzustki, rakowiaka albo pheochromocytoma.
Summary
Chromogranin A (CgA) is a main nonspecific neuroendocrine tumour (NET) marker. Currently few commercial assays are available: RIA, IRMA, ELISA, CLIA, TRACE. There are many factors: in vivo, in vitro and coexisting diseases which can influence the CgA blood concentration. Elevated CgA levels in blood can be usually detected in: gastroenteropancreatic neuroendocrine tumours (GEP-NET), pheochromocytoma, neuroblastoma, MEN syndromes, bronchopulmonary NETs, medullary thyroid carcinoma, small-cell lung carcinoma, and some other very rare NETs. CgA measurement became a routine investigation in the diagnosis of GEP-NET, but is especially helpful in monitoring the effects of their treatment. CgA can be considered as a complementary investigation in the diagnostic procedure of pheochromocytoma. In patients with multiple endocrine neoplasia (MEN) investigation of CgA level may be used in monitoring eventual coexistence or appearance with time of carcinoid, pancreatic neuroendocrine tumour or pheochromocytoma.



Introduction
Chromogranin A (CgA) is present in some endocrine cells of adrenals, pituitary, pancreas, thyroid and in cells of diffuse endocrine system (DES) of gastrointestinal and respiratory system. It is co-secreted and co-released together with some amines and peptides, that are present in the neurosecretory granules. In functionally active, and non-active neuroendocrine tumors (NETs) blood CgA level is often elevated, therefore, it is accepted as a main nonspecific marker of NETs (1, 2).
Chromogranin A: structure and biological function
Chromogranin A is an acidic protein with a molecular weight of 48 kDa that is composed of 439 amino acids (3). The human CgA gene (CHGA) is located on chromosome 14 (4). There are 10 dibasic sites in human CgA, which are potential sites for proteolytic cleavage (5). CgA occurs in two main conformations: random coil (60-65%) and alpha-helix (25-40%). Alteration of CgA conformation is pH and calcium ions dependent (6, 7). CgA is a protein binding Ca2+ ions. Many regions of CgA are homologous with Ca2+ binding protein – calmodulin (8). CgA is a member of the chromogranin family. The granin family consists of eight proteins including: CgA, chromogranin B (CgB), secretogranin II, secretogranin III, secretogranin IV, secretogranin V, secretogranin VI, VGF (9). Posttranslational processing of CgA molecule leads to the formation of smaller biologically active peptides, such as: vasostatin I, vasostatin II, chromacin, pancreastatin, WE-14, parastatin, catestin (10). These CgA-derived peptides due to their influence on the secretion of other hormone, play an indirect role in the metabolism of lipids, carbohydrates, calcium homeostasis, catecholamine secretion, and possess some activities on the cardiovascular system (e.g. vasoconstriction, vasodilatation). They participate also in regulation of secretion of some hormones (e.g. insulin, glucagon, leptin, LH, FSH, PTH), and play some role in the defense mechanism of the respiratory system (antimicrobial activity against bacteria, fungi) (11-15).
Pre-analytical and analytical aspects of chromogranin A (CgA) measurement in blood
Measurement of blood CgA concentration appeared possible despite the presence in blood of circulating CgA fragments induced by proteolysis (16).
The first radioimmunoassay for measurements of chromogranin A was introduced by O’Connor and Bernstein in 1984 (17). The next generation assays were based on sandwich methods with the use of monoclonal or polyclonal antibodies (18). Currently few commercial assays are available: IRMA (CgA-RIA CT, CIS Bio International-Schering, Gif-sur-Yvette, France), DAKO chromogranin A ELISA kit (DAKO A/S, Glostrup, Denmark), RIA (EuroDiagnostica, Malmo, Sweden), TRACE (Kryptor System; B-R-A-H-M-S GmbH, Thermo Scientific, Germany). These assays differ in test structure, use different antibodies and differently calibrated standards. The applied in these assay monoclonal or polyclonal antibodies recognize different epitopes of CgA molecule and bind also some CgA fragments (19-21). Main characteristics of the mentioned method for determination of CgA are presented in table 1.
Table 1. Comparison of the currently available methods for determination of CgA concentration.
MethodKit producerAntibodyStandardUnitSort of biological material
(according to the
kit producer)
Upper reference
range
(according to the kit producer)
Immunoradiometric
(IRMA)
CIS Bio2 monoclonalrh CgAng/mlserum
plasma
serum
98 ng/ml
plasma?
ELISACIS Bio2 monoclonalrh CgAng/mlserum
plasma
serum
98 ng/ml
plasma?
ELISADAKO 2 polyclonal23 kDa C-terminal fragment of CgAU/lplasma
(EDTA, heparin)
serum?
plasma
2-18 U/l
Radioimmunoassay
(RIA)
EuroDiagnostica1 polyclonalCgA fraction purified from urine (patients with carcinoid tumours)nmol/lserum
plasma
(EDTA, heparin)
serum and plasma
≤ 3 nmol/l
ELISAALPCO2 polyclonalrh CgAng/mlplasma (EDTA)serum?
plasma
100 ng/ml
Automated immunometric
assay (Kryptor)
 
B-R-A-H-M-S2 monoclonalrh CgAμg/lserumserum
male: 84.7 μg/l
female: 43.2 μg/l
plasma?
rh CgA – human recombinant CgA
Lack of the recognized international standard for CgA, differences of methodology and specificity of the antibodies used, cause that individual CgA measurements performed with different CgA assays cannot be directly compared (22-23).

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otrzymano: 2014-10-15
zaakceptowano do druku: 2014-11-07

Adres do korespondencji:
*Piotr Glinicki
Department of Endocrinology The Centre of Postgraduate Medical Education Bielański Hospital
ul. Cegłowska 80, 01-809 Warszawa
tel. +48 (22) 569-02-93
fax +48 (22) 834-31-31
glinicki@cmkp.edu.pl

Postępy Nauk Medycznych 12/2014
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