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Copeptin and Its Potential Role in Diagnosis and Prognosis of Various Diseases Lidija Dobša*1, Kido Cullen Edozien2

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Copeptin and Its Potential Role in Diagnosis and Prognosis of Various Diseases Lidija Dobša*1, Kido Cullen Edozien2 Review Copeptin and its potential role in diagnosis and prognosis of various diseases Lidija Dobša*1, Kido Cullen Edozien2 1Health Institution Varaždin County, Medical Biochemistry Laboratory, Varaždin, Croatia 2Mater Dei Hospital, Msida, Malta *Corresponding author: [email protected] Abstract The need for faster diagnosis, more accurate prognostic assessment and treatment decisions in various diseases has lead to the investigations of new biomarkers. The hope is that this new biomarkers will enable early decision making in clinical practice. Arginine vasopressin (AVP) is one of the main hormones of the hypothalamic-pituitary-adrenal axis. Its main stimulus for secretion is hyperosmolarity, but AVP system is also stimulated by ex- posure of the body to endogenous stress. Reliable measurement of AVP concentration is diffi cult because it is subject to preanalytical and analytical errors. It is therefore not used in clinical practice. Copeptin, a 39-aminoacid glycopeptide, is a C-terminal part of the precursor pre-provasopressin (pre-proAVP). Activation of AVP system stimulates copeptin secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore, copeptin directly refl ects AVP concentration and can be used as surrogate biomarker of AVP secretion. Even mild to moderate stress situations contribute to release of copeptin. These reasons have lead to a handful of research on copeptin in various diseases. This review sum- marizes the current achievements in the research of copeptin as a diagnostic and prognostic marker and also discusses its association in diff erent disease processes. Key words: human copeptin; endogenous stress; diagnostic accuracy; prognosis Received: November 29, 2012 Accepted: May 01, 2013 Introduction Copeptin, a 39-aminoacid glycopeptide is a C-ter- any signifi cant function in the circulation (6). minal part of pre-provasopressin (pre-proAVP). Copeptin is cosynthesized with AVP and is found Pre-proAVP is a precursor protein which consists in equimolar amounts with AVP in the circulation of a signal peptide, arginine vasopressin (AVP), of healthy and critically ill subjects (7,8). Thus neurophysin II and copeptin (1-3). These compo- copeptin mirrors AVP concentration and can be nents are separated during axon transport from used as a replacement biomarker of AVP release the cell body to the axon terminals in the posterior (6,7). pituitary gland (3). On the path from the hypotha- For certain diseases, diagnosis and prognosis can lamus to the pituitary gland, copeptin and neuro- still be very demanding and time-consuming. This physin II act as carrier proteins of AVP. Copeptin is is why new biomarkers are needed to aid clinicians stored in the neurohypophyseal vesicles together in making faster treatment decisions and more ac- with AVP and neurophysin II until they are secret- curate prognostic assessment. To be of practical ed (4). Schematic presentation of copeptin genera- value, a new biomarker needs to provide quantita- tion and maturation is shown in Figure 1. Copeptin tive information that is both reliable and reproduc- also has a very important role in the proteolysis of ible. Moreover, the measurement of a biomarker pre-proAVP, but its main role in the circulation is should be easy, rapid and inexpensive to perform. still unknown (3,6). Slow degradation of copeptin Therefore, copeptin has been proposed as a prog- in humans hints that this peptide may not have nostic marker in diff erent illnesses and disorders Biochemia Medica 2013;23(2):172–90 http://dx.doi.org/10.11613/BM.2013.021 172 Dobša L, Edozien KC. Copeptin and diseases when compared to men, but there is no signifi cant Synthesis of pre-pro-AVP in the magnocellular nuclei of the diff erence in copeptin rise between men and hypothalamus women with changes in osmolality or volume sta- Cleavage of the signal peptide tus (3,12,13). Renal function also infl uences copep- tin concentration in healthy men and this is not Pro-AVP folds, placing AVP into a binding pocket of neurophysin noticed in healthy women (12). Copeptin has not II, protecting it from proteolysis being found to correlate with age or estimated and promoting high-density packing in neurosecretory glomerular fi ltration rate in healthy subjects, ex- vesicles cept in patients with AMI where copeptin concen- Formation of seven disulfide tration correlates with age and estimated glomer- bonds within neurophysin II ular fi ltration rate (9,12,13). In advanced and acute and one within AVP; glycosylation of copeptin heart failure the rise in copeptin concentration goes from 20 pmol/L to 45 pmol/L. In terms of life Pro-AVP is packaged into neurosecretory granules threatening conditions, such as severe sepsis, sep- tic shock, hemorrhagic shock, ischemic stroke and Cleavage of pro-AVP that splits During axonal transport from AMI, copeptin increases to concentrations above off AVP the hypothalamic nuclei to the neutrohypophysis 100 pmol/L. On the opposite sphere, copeptin de- Cleavage that separates creases in patients with diabetes insipidus, hy- neurophysin II from copeptin Processing is complete at the level of the neurohypophysis ponatremia and other conditions associated with reduced AVP concentration (13). It is still however FIGURE 1. Schematic presentation of copeptin generation and unknown how copeptin is removed from the cir- maturation (5). culation. It is assumed that it is partially cleared through the kidneys because it is detectable in urine (7). where it may help in early detection and diagnos- tic accuracy. The purpose of this review is to sum- Function of AVP marize a handful of research done on copeptin and to discuss its role as a biological marker in the AVP is a vasoactive neuropituitary hormone. It is diagnosis and prognosis of various diseases such one of the main hormones of the hypothalamic- as acute myocardial infarction (AMI), heart failure, pituitary-adrenal axis and its primary function is hyponatremia, sepsis, septic shock, infections of water regulation and homeostasis of electrolytes. lower respiratory tract, acute dyspnea, vasodilato- The main stimulus for AVP release is hyperosmo- ry shock, diabetes insipidus, autosomal dominant larity. Hypotension, hypoxia, acidosis, infection, in- polycystic kidney disease (ADPKD), diabetes melli- sulin-induced hypoglycemia, pain, nausea, vomit- tus, metabolic syndrome, intracerebral hemor- ing, certain drugs and other non-specifi c causes of rhage, ischemic stroke and head injury. stress can also increase concentration of AVP in the circulation (3,7). Copeptin in circulation AVP binds to 3 diff erent receptors, V1a, V1b and V2 receptor. They are classifi ed into three subtypes Normal values of copeptin in healthy volunteers based on their intracellular transduction mecha- range between 1.70-11.25 pmol/L (6,9,10). Copep- nisms. The V1a and V1b receptors are associated tin also shows minimal intra-individual variations with phosphoinositol turnover, while the V2 recep- (11). In healthy people, a 28h water deprivation tor activates adenylate cyclase (14). The V1a recep- leads to a twofold increase in concentration of tor is widely expressed and mediates AVPs pro- copeptin, while infusion of hypotonic saline induc- thrombotic and vasoconstrictor eff ects. Thus, AVP es a 2-3-fold decrease of copeptin concentration agonists are used in treating bleeding and hypo- (11). Copeptin concentration are lower in women tensive disorders (15-17). Through V1a receptor http://dx.doi.org/10.11613/BM.2013.021 Biochemia Medica 2013;23(2):172–90 173 Dobša L, Edozien KC. Copeptin and diseases AVP also mediates liver glycogenolysis (16,17). The V1b receptor is expressed in the pituitary gland tracer antibody and pancreas (15,16). Through this receptor AVP stimulates the release of adrenocorticotropic hor- mone. Adrenocorticotropic hormone activates the hypothalamic-pituitary-adrenal axis and thus me- COPEPTIN diates a response to stress. Insulin and glucagon secretion are mediated via V1b receptor as well (16,17). The V2 receptor is expressed in the renal antibody on tube collecting ducts and through those receptors the antidiuretic eff ect of AVP is mediated (15,16). Phar- solid phase macological blockade of V2 receptor has been used to treat hyponatremia and heart failure FIGURE 2. Scheme of assay for the measurement of copeptin. (16,17). Measurement of AVP and copeptin Reliable measurement of plasma AVP concentra- Unlike AVP, copeptin is stable in EDTA plasma for tion is diffi cult and is subject to preanalytical and up to 14 days at room temperature, while in citrate analytical errors. Such diffi culties stem from fact and heparin plasma copeptin is stable for 7 days that AVP is unstable due to its short half-life of 24 (19). Its detection doesn’t require extraction or min. To add to this problem, more than 90% of other complex preanalytical steps (13). It can easily AVP in the circulation is bound to platelets, thus be measured ex vivo by manual or fully automated making accurate measurements very diffi cult chemiluminescence assays as a replacement bi- (3,6,18,19). Incomplete removal of platelets from omarker for unstable AVP (1,20,21). Scheme of as- plasma samples or prolonged storage of unproc- say for the measurement of copeptin is shown in essed blood samples can lead to falsely elevated Figure 2. The assay requires minimal serum or plas- values of AVP. AVP is also unstable in isolated plas- ma volume and the overall time for completing ma and serum even when it is stored at -20 °C the analysis is between 20 and 30 minutes (13). (6,13). The small size of AVP also challenges detec- Based on these facts, copeptin is suitable for rou- tion by sandwich immunoassays and therefore re- tine measurements as an alternative to AVP (6). quires the use of less sensitive competitive immu- Some of the methodology characteristics for cope- noassays (13). All the above mentioned reasons ptin and AVP assays are summarized in Table 1.
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