Endocrine Abstracts

Introduction: The syndrome of inappropriate antidiuresis (SIADH) is the most common cause of hypoosmolality. Ectopic AVP hypersecretion has long been considered as the primaryn mechanism of SIADH. But different types of osmoregulatory defect in AVP release have been described in this disorder. A comprehensive characterization of these different forms of SIADH in a large cohort of patients may provide important new insights into the still incompletely understood pathophysiology of SIADH, as well as the variable need for therapeutic management in SIADH.

Methods and design: Differences in pathological AVP osmoregulation in SIADH were characterized by serial measurement of plasma copeptin, a reliable AVP surrogate marker, in 50 patients with SIADH during osmotic stimulation. The physiological relationship between plasma copeptin and osmolality was defined by means of 68 healthy controls, who underwent the same protocol of osmotic stimulation.

Results: In healthy subjects, a close correlation was found between plasma copeptin and osmolality with an osmotic-threshold of 282±4.3 mOsm/kg H₂O. In SIADH, five different types of defective AVP osmoregulation were found: 10% of patients showed a markedly elevated and osmotically-independent form of copeptin release (type A); 14% demonstrated a linear osmotic response to rising serum osmolality, but with an abnormally low osmotic-threshold (type B); 44% revealed a fixed, plateau-like copeptin secretion (type C); and 12% of patients had an AVP-independent SIADH with undetectable copeptin levels. A different, new type of SIADH was found in 20% of patients, demonstrating an inverse relation of decreasing plasma copeptin levels to increasing osmolality (type E).

Conclusion: These findings confirm the concept of ectopic AVP secretion (type A) and AVP-independent antidiuresis (type D) as osmodefective subtypes of SIADH. But the main pathophysiological alteration in most patients with SIADH was the profound impairment of AVP osmoregulation well into the normoosmotic range. Moreover, firstly a novel subtype of SIADH could be described, presumably related to impaired nonosmotic inhibitory pathways in combination with altered osmoregulatory function.