Copeptin as a marker for arginine-vasopressin/antidiuretic hormone secretion in the diagnosis of paraneoplastic syndrome of inappropriate ADH secretion.

Direct measurement of arginine-vasopressin/antidiuretic hormone (AVP/ADH) concentrations is not included in the standard diagnostic procedures for paraneoplastic syndrome of inappropriate ADH secretion (SIADH). Here, we evaluate the potential of copeptin measurement as a surrogate marker of AVP/ADH secretion for the direct diagnosis of suspected SIADH in cancer patients. Forty-six unselected cancer patients with serum sodium concentrations permanently below 135 mmol/L were included in this study. We compared standard diagnostic criteria for SIADH to the measurement of plasma copeptin in relation to osmolality. Normative data for comparison were constructed from 24 healthy controls studied under basal conditions, experimental dehydration, and hypotonic hypervolemia as well as from 222 hospital patients with no suspicion of an altered ADH regulation. Log transformation of copeptin revealed a linear relationship to plasma osmolality in the controls (R = 0.495, p < 0.001). Compared to these normative data, copeptin levels in most cancer patients were inappropriately high for plasma osmolality and were not significantly correlated. These results, suggestive for paraneoplastic SIADH, could be confirmed by conventional diagnostic procedures for SIADH. Current strategies to diagnose SIADH are difficult to perform under outpatients conditions. Our approach allows screening from a single plasma sample for true paraneoplastic ADH oversecretion and thus rapid selection for a specific therapy with an AVP receptor antagonist.

Licorice - or more?

A 57 yr old man presented to endocrinology clinic with a six year history of poorly controlled hypertension which was treated with Metoprolol 200 mg/day and Enalapril 20 mg/day. He was asymptomatic but incidentally hypokalaemia was detected while having cholecystectomy, two years prior to his clinic appointment. He had never been on diuretics or laxatives. He was started on potassium supplements (120 mmol/d) and advised to increase dietary potassium by the surgical team. A detailed personal history revealed ingestion of 300-500 g licorice per day. Physical examination was unremarkable apart from increased blood pressure of 180/105 mmHg. Following the initial visit, his serum electrolyes (K+3.7 mmol/l) were normal with potassium supplementation and as were morning cortisol, ACTH, 11-deoxycortisol and plasma metanephrines. 17 OH-P, DHEAS and androstenedione were normal but testosterone was low. Morning ambulant aldosterone was slightly increased at 801 pmol/L and renin activity was undetectable. Urinary 24 h aldosterone excretion was significantly increased at 162 ng/24 h with normal cortisol and catecholamine excretion. Four weeks following advice to stop licorice, serum potassium decreased to 3.4 mmol/L despite continuous supplementation. Morning plasma aldosterone increased to 1 449 pmol/ml, renin activity remained undetectable but 24 h urine aldosterone excretion increased to 434 ng/24 h with a reduction in urinary cortisol excretion. Interestingly 17 OH-P and androstenedione levels, although within the reference range, were slightly higher compared to the levels whilst on licorice. Testosterone level had significantly increased to be within normal range. Abdominal imaging with US and MRI showed a 2.7 cmx2.2 cmx1.7 cm left adrenal mass. He underwent laparoscopic left adrenalectomy and histology confirmed aldosterone producing adrenal adenoma. Post-operatively his aldosterone and serum potassium levels normalized and he became normotensive without any antihypertensive medication.

Following brain trauma, copeptin, a stable peptide derived from the AVP precusor, does not reflect osmoregulation but correlates with injury severity.

The incidence of water and electrolyte disturbances following traumatic brain injury (TBI) is considerable and has been attributed to a dysregulation of the hypothalamic peptide arginine-vasopressin (AVP). Copeptin, the C-terminal part of the AVP prohormone, reflects AVP activity. In 71 TBI patients we measured copeptin in serum by a sandwich immunoassay. Injury severity was assessed by Glasgow Coma Score (GCS) and computed tomography, and recovery by Glasgow Outcome Score (GOS). Neuroendocrine and osmoregulation regulation were examined on day 0, 3 and 7, and 24 months post-injury. Copeptin was highest on admission (40.0 +/- 72.3 pmol/l), stabilized on day 3 and 7 (21.2 +/- 18.3 resp. 20.3 +/- 17.1 pmol/l), and normalized at follow-up (4.2 +/- 1.7 pmol/l). On admission, there was a correlation between serum sodium and urine excretion (p = 0.003), but the correlation got lost on day 3 and 7. Copeptin did not reflect the individual 24 h urine excretion or serum sodium levels indicating an uncoupling of copeptin/AVP release and renal water excretion. High copeptin level on day 3 were correlated with a low GCS (p < 0.001), midline shift (p = 0.019), intracerebral hemorrhage (p = 0.026), SAPS score (p = 0.001), as well as with a low GOS (p = 0.031). Copeptin was significantly decreased following skullbase fracture (p = 0.016).Our data reveal a loss of hypothalamic osmoregulation following TBI. The measurement of Copeptin/AVP release reveals a significant predictive function for the severity of TBI.