Serum Copeptin
Blood Tests

Author: Tania Villanova
Date: 08/09/2014

Description

Giulia Francescato
Tania Villanova

COPEPTIN

PRE-PROAVP

Arginine vasopressin (AVP), also termed antidiuretic hormone, is a nine-amino acid peptide with a disulfide bridge between two cysteine amino acids. It is synthesized in the magno- and parvocellular neurons of the paraventricular and supraoptic nuclei of the hypothalamus and it is stored and secreted by granules within the posterior lobe of the pituitary, primarily as a response to high plasma osmolality, low plasma volume, and/or low blood pressure.
The main role of AVP is to induce water conservation by the kidney, contributing to the regulation of osmotic and cardiovascular homeostasis. By increasing water permeability of the apical membrane of renal collecting duct cells, AVP promotes free water reabsorption and is therefore one of the key regulators of the body’s water and solute balance. A rise in plasma osmolality above 280 mOsm/kg is the main stimulus for AVP release.
It also has hemostatic, endocrine and central nervous effects.
To a lesser extent, it is also produced in other tissues including the sympathetic ganglia, adrenal glands, and the testis.
AVP is derived from a larger precursor peptide, the pre-provasopressin, which consists of a signal peptide, arginine vasopressin (AVP), neurophysin II and copeptin (CTproAVP).
In neurosecretory granules, the hormone precursor is proteolytically processed to yield AVP, neurophysin II, and copeptin, which are cosecreted from the posterior pituitary.
Neurophysin II has a complex structure with many putative intramolecular disulfide bonds, and it may be associated with AVP during maturation and transport. Copeptin, the C- terminal portion of pre-provasopressin, is a 39-amino acid glycopeptides that may have a role during the intracellular processing of provasopressin, possibly contributing to correct structural formation of the precursor, which leads to efficient proteolytic maturation.

These components are separated during axon transport from the cell body to the axon terminals in the posterior pituitary gland. On the path from the hypothalamus to the pituitary gland, copeptin and neurophysin II act as carrier proteins of AVP. CTproAVP is stored in the neurohypophyseal vesicles together with AVP and neurophysin II until they are secreted.

- Copeptin and its potential role in diagnosis and prognosis of various diseases, Biochemia Medica 2013

- Correlation of Plasma Copeptin and Vasopressin Concentrations in Hypo-, Iso-, and Hyperosmolar States

- Laycock JF. Introduction to vasopressin. In: Perspectives on vaso- pressin. London: World Scientific Publishing Company, Imperial College Press, 2010;1–16.

COPEPTIN (CTproAVP)

The concentration of copeptin in the blood circulation ranges from 1 to 12 pmol/L in healthy individuals. The levels of copeptin are slightly higher in men than in women and are not influenced by age.The physiological role of copeptin is unknown.
Activation of AVP system stimulates copeptin secretion into the circulation from the posterior pituitary gland in equimolar amounts with AVP. Therefore, CTproAVP directly reflects AVP concentration and can be used as surrogate biomarker of AVP secretion. Even mild to moderate stress situations contribute to the release of CTproAVP. These reasons have led to several different lines of research in various disease states.
Reliable measurement of AVP is hindered by several factors and validated AVP assays are therefore scarce. More than 90% of circulating AVP is bound to platelets, resulting in either underestimation or, in case of prolonged storage of unprocessed blood samples at room temperature, falsely elevated AVP levels. As a consequence of these technical drawbacks and the paucity of reliable commercially available AVP assays, measurement of circulating AVP levels is not usually part of clinical routine diagnostics.
To overcome some of these disadvantages, CTproAVP can be used as a surrogate for AVP since it is very stable in plasma and during storage. Unlike AVP, it does not require any pre-analytical processing and can be easily deter- mined with several manual and automated assays.
Studies have shown that CTproAVP mirrors AVP levels under diverse physiologic and pathophysiologic conditions such as changes in plasma osmolality, stress and various disease states. The measurement of CTproAVP can be used to reflect AVP concentrations as it is produced in equimolar amounts as AVP and released into the circulation at the same time as AVP secretion

- Wikipedia

- Balanescu S, Kopp P, Gaskill MB, Morgenthaler NG, Schindler C, Rutishauser J. Correlation of plasma copeptin and vasopressin concentrations in hypo-, iso-, and hyperosmolar states. J Clin Endocrinol Metab 2011;96:1046–52.

Measurement of copeptin
 
The small size of AVP also challenges detection by sandwich immunoassays and therefore requires the use of less sensitive competitive immunoassays. All the above mentioned reasons contribute to the absence of routine AVP use in clinical practice.
Unlike AVP, copeptin is stable in EDTA plasma for up to 14 days at room temperature, while in citrate and heparin plasma copeptin is stable for 7 days. Its detection doesn’t require extraction or other complex preanalytical steps. It can easily be measured ex vivo by manual or fully automated chemiluminescence assays as a replacement biomarker for unstable AVP. The assay requires minimal serum or plasma volume and the overall time for completing the analysis is between 20 and 30 minutes. Based on these facts, copeptin is suitable for routine measurements as an alternative to AVP. 

- Assay for the Measurement of Copeptin, a Stable Peptide Derived from the Precursor of Vasopressin

- Copeptin and its potential role in diagnosis and prognosis of various diseases, Biochemia Medica 2013

Copeptin as a diagnostic and prognostic marker

In stressful situations such as illness, the relationship between plasma osmolality and AVP is lost because AVP with corticotropin-releasing hormone (CRH) leads to the production of adrenocorticotropic hormone (ACTH) and cortisol. Serum cortisol is proportional to stress levels, and by reflecting stress levels, cortisol predicts prognostic outcome in different diseases. However, cortisol is influenced by strong circadian rhythm and its measurement as a free hormone is demanding. These characteristics of cortisol place CTproAVP as a more reliable hormone for determination of stress levels. Of note, even mild to moderate stress situations contribute to the copeptin release.
In recent years copeptin has been studied as a diagnostic marker and as a prognostic marker in different diseases. As a diagnostic marker, copeptin was evaluated in patients with diabetes insipidus, for example, after pituitary surgery. In these patients copeptin had a superior diagnostic accuracy to detect an insufficient activity of the posterior pituitary, offering an alternative to the laborious and ambiguous water-deprivation test.
Diabetes insipidus (DI) is a clinical syndrome characterized by polyuria due to a defect in the urinary concentrating mechanism .There is also an associated compensatory polydipsia. The prevalence in the general population is estimated at 1 per 25–35,000. The syndrome comprises three main types central, nephrogenic and gestational, and a related syndrome, primary polydipsia.
Central (neuro-hypophyseal) DI is associated with impaired production or secretion of AVP, such as in pituitary injury after head trauma or surgery. It is estimated that 20%–30% of pituitary operations are associated with transient central DI, and that 2%–10% lead to permanent disease
An accurate differentiation of the underlying pathology is necessary for effective treatment of DI. If the patient has central diabetes insipidus, the AVP concentration will not increase – even though there has been a significant decrease in body weight or increase in plasma osmolarity. However, if the patient has nephrogenic DI, AVP will appropriately increase in parallel to dehydration status progression and the increase in plasma osmolarity. Desmopressin (an exogenous synthetic vasopressin analog) is commonly administered as a challenge after water deprivation to see if there is a further change in urine osmolality. Nephrogenic DI is characterized by impaired AVP- induced water adsorption. Acquired nephrogenic DI is most commonly associated with electrolyte abnormalities (such as hypokalemia or hypercalcemia) or the therapeutic use of drugs, such as lithium or cisplatin.
Gestational DI, is due to an increased degradation of AVP from vasopressinase, a placental enzyme. Although it is not very commonly observed, it can be under diagnosed, as polyuria is considered normal during pregnancy.
DI should be differentiated from primary polydipsia.
CTproAVP has been used in several recent studies as a novel approach for the diagnosis of DI. This method evaluates osmotically stimulated CTproAVP after an 8-h water withdrawal period. The first blood sample is able to aid in the distinction between central complete and nephrogenic DI by comparing the plasma levels of CTproAVP. Concentrations of CTproAVP that are <2.6 pmol/L indicate central DI complete whereas concentrations >20 pmol/L indicate nephrogenic DI. Patients with intermediate values between 2.6 and 20 pmol/L undergo a further 8 h of fluid deprivation.
Patients with a CTproAVP index of <20 are classified as having partial central DI whereas patients with values >20 have primary polydipsia
As a prognostic marker, copeptin levels were independent predictors of survival in critically ill patients suffering from hemorrhagic and septic shock. In lower respiratory tract infections, the copeptin levels were significantly higher as compared with control individuals, with the highest levels in patients with community-acquired pneumonia. Copeptin levels increased with increasing severity of pneumonia, as classified by the pneumonia severity index. Similarly, in patients with acute exacerbations of chronic obstructive pulmonary disease, copeptin was shown to be predictive of long-term clinical failure independent of age, comorbidity, hypoxemia and lung functional impairment in multivariate analysis.
Several studies have shown that increased CTproAVP concentration is a strong predictor of mortality in patients with chronic heart failure, acute heart failure and heart failure caused by acute myocardial infarction.

- Robertson GL. Diabetes insipidus. Endocrinol Metab Clin North Am 1995;24:549–72.

- Copeptin: a new and promising diagnostic and prognostic marker, Crit Care. 2008

- Copeptin and its potential role in diagnosis and prognosis of various diseases, Biochemia Medica 2013

- Morgenthaler NG, Struck J, Alonso C, Bergmann A. Assay for the measurement of copeptin, a stable peptide derived from the precursor of vasopressin. Clin Chem 2006

CONCLUSION

CTproAVP can be used instead as a surrogate to provide insight on AVP, as it is produced at the same time, has high plasma stability and is easy to measure.
Since it is not specific to a certain disease, copeptin could be used as an adjunct with more specific biomarkers where it may increase diagnostic accuracy and aid clinicians in making better diagnostic judgements.

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