Clinical characteristics and novel diagnostic tests in patients with arginine vasopressin deficiency (central diabetes insipidus)

Background: Arginine vasopressin (AVP) deficiency (central diabetes insipidus) is a neuroendocrine condition characterised by polyuria and polydipsia. The diagnostic evaluation in case of suspected AVP deficiency is challenging and simplified approaches with high diagnostic accuracies are needed. Once correctly diagnosed with AVP deficiency treatment with desmopressin (AVP receptor analogue) is started to control for polyuria. However, desmopressin treatment is accompanied by a high prevalence of hyponatremia. On the other hand, restriction to desmopressin and fluid intake during hospitalisation, partly explained by confusion with ‘diabetes mellitus’, may lead to severe consequences. Data on methods to counteract the risk of hyponatremia and data on treatment errors during hospitalisations are lacking. Additionally, hypothalamic-pituitary disruptions leading to AVP deficiency could also disturb the oxytocin system with subsequent clinical consequences. However, oxytocin deficiency has never been defined as pituitary entity and no provocation test is available to test for an oxytocin deficiency.
Objective: First, to investigate whether the glucagon provocation test might provide a novel diagnostic test in the differential diagnosis of AVP deficiency. Second, to assess patients' perspectives regarding their disease management, psychological comorbidities, and view for renaming ‘diabetes insipidus’ to avoid confusion with ‘diabetes mellitus’. And third, to investigate 3,4-methylene-dioxymethamphetamine (MDMA) as a novel provocation test to reveal an OXT deficiency.
Methods: The first study is a double-blind, randomised, placebo-controlled trial including 22 healthy controls, ten patients with AVP deficiency, and ten patients with primary polydipsia (PP). The second study is a cross-sectional, web-based survey including 1034 patients with AVP deficiency. The third study is a randomised, placebo-controlled, double-blind, cross-over trial including 15 patients with AVP deficiency and 15 matched healthy controls.
Results: First, in patients with AVP deficiency, copeptin showed no relevant increase in response to glucagon, whereas copeptin was strongly stimulated in patients with primary polydipsia (PP). Glucagon stimulation demonstrated a high diagnostic accuracy in differentiating between both conditions. Second, once diagnosed and treated with desmopressin, a high prevalence of hyponatremia leading to hospitalisations was observed. Patients who routinely omitted or delayed desmopressin to allow intermittent aquaresis had a significantly lower prevalence of hyponatraemia than those unaware of this approach. Of patients who had to be hospitalised for any medical reason, one in seven reported symptoms of dehydration due to desmopressin restriction or/and wrong fluid management. One in three patients reported psychological changes subjectively associated with their AVP deficiency. In total, 85% of patients supported renaming the disease. Third, in patients, there was only a minimal OXT increase in response to MDMA, while in healthy controls, there was a robust eight-fold OXT increase.
Discussion: First, glucagon-stimulated copeptin has the potential for a safe, novel, and precise test in the differential diagnosis of AVP-D. Second, our data show a high prevalence of treatment-associated side-effects, mismanagement during hospitalisation, psychological comorbidities, and clear support for renaming the disease; our data are the first to indicate the value of routinely omitting or delaying desmopressin. Third, these results lay the basis for OXT deficiency as a new hypothalamic-pituitary entity.