Browse the corpus

Diabetes Insipidus (DI) is the excess production of dilute urine. Because of the confusion with Diabetes Mellitus, there has been a move to renaming this to AVP-Deficiency (AVP-D; Central Diabetes Insipidus) and AVP-Resistance (AVP-R; Nephrogenic Diabetes Insipidus). Diagnosis requires a targeted history, examination, and confirmation through appropriate laboratory and radiological investigations. AVP-D and AVP-R present with polyuria and polydipsia. Urine output is more than 50 ml/kg /24 hours in adults and more than 100 ml/kg/24 hours in children. The condition reflects either the lack of production or action of the posterior pituitary hormone vasopressin (AVP). There are three subtypes. • AVP-Deficiency (Cranial or hypothalamic DI; HDI): due to relative or absolute lack of AVP. • AVP-Resistance (Nephrogenic DI; NDI): due to partial or total resistance to the renal antidiuretic effects of AVP. • Primary Polydipsia (PP; Dipsogenic DI; DDI): where polyuria is secondary to excessive, inappropriate fluid intake. All forms are rare. AVP-D has an estimated prevalence of 1/25,000. While presentation is more common in adults, familial forms characteristically present in childhood.

A VP is a nine-amino acid peptide made within magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei of the hypothalamus that project through the hypophyseal portal tract to terminate in the posterior pituitary, where AVP is released into the circulation. Together, the PVN, SON and posterior pituitary form an anatomical and functional unit- the neurohypophysis (). AVP is produced from a large precursor that undergoes extensive post-translational processing (). The major action of AVP is in the regulation of renal water excretion. AVP increases expression of the AVP-dependent water channel Aquaporin 2, which is expressed in the renal collecting duct, facilitating water reabsorption. This action of AVP is mediated by the type 2 AVP receptor (V2-R), expressed exclusively on the interstitial surface of target cells in the distal nephron. AVP release is regulated by osmoreceptors within the lamina terminalis. There is a linear relationship between plasma osmolality and plasma AVP concentration. Not unexpectedly, thirst perception is regulated in a parallel manner ().

Presentation with AVP-D implies loss of 80%-90% of AVP production from the posterior pituitary. This, in turn, reflects either destruction of vasopressinergic magnocellular neurons in the hypothalamus or interruption of intra-axonal transport/processing of AVP. Some 50% of children and young adults with AVP-D have an underlying tumor or CNS malformation (e.g. craniopharyngioma, germinoma, septo-optic dysplasia). Familial AVP-D comprises 5% of cases. Acute AVP-D can occur in up to 22% of non-selected patients presenting with traumatic brain injury (TBI), persisting in some 30% of these on long term follow up. AVP-D may follow trauma to the pituitary or hypothalamus. AVP-D following surgery to the pituitary or neurohypophysis presents within 24-48h after surgery and is often transient, resolving within 10 days. Pituitary stalk trauma (including that following surgery) may lead to a tri-phasic disturbance in water balance; an immediate polyuria due to AVP-D followed by a more prolonged period of antidiuresis suggestive of AVP excess. The antidiuretic phase may last several weeks and can be followed by reversion to AVP-D or recovery. AVP-D presenting with a pituitary mass should raise concerns about a diagnosis other than pituitary adenoma. AVP-D can worsen in pregnancy due to increased degradation of AVP by placental enzyme activity.

Renal resistance to AVP may reflect a toxic renal tubulopathy secondary to metabolic (e.g. hypokalemia; hypercalcemia), medical disorders (e.g. sarcoidosis, amyloidosis, sickle cell anemia, multiple myeloma, etc.), or drug effects (e.g. lithium, demeclocycline, cisplatin, etc.). Prolonged polyuria of any cause can result in partial AVP-R through disruption of the intra-renal solute gradients and reduced tubular concentrating capacity. X-linked familial AVP-R results from loss-of-function mutations in the renal AVP receptor (). Autosomal recessive AVP-R is caused by loss-of-function mutations in the AVP-dependent renal water channel aquaporin-2.

Persistent high fluid intake leads to appropriate polyuria. If intake exceeds the limit of renal free water excretion, hyponatremia may result. Primary Polydipsia can be associated with abnormalities in thirst perception. • Exaggerated thirst response to osmotic challenge. • Inability to suppress thirst at low plasma osmolalities. Neuroimaging is normal in most cases. Primary Polydipsia is associated with affective disorders.

• Associated endocrinopathy: suggestive of additional hypothalamic or pituitary dysfunction. • Neuro-ophthalmic problems suggestive of structural disease. • Evidence of drug toxicity (e.g. lithium, phenytoin). There should be a standard initial diagnostic approach. • Confirmation of true polyuria, distinct from simple frequency without excess urine volume. • Exclusion of common differentials such as drug (diuretics) and metabolic causes (hyperglycemia, hypercalcemia hypokalemia). If polyuria is confirmed and simple causes are excluded, the clinician should consider a copeptin-based test which is a direct assessment of AVP production and action in response to osmolar stress or a Water Deprivation Test (). Copeptin is one of the peptides contained within pre-pro-vasopressin and is a good surrogate marker of AVP production. A basal copeptin < 4.9pmol/L in the context of other pituitary hormone loss and nocturia suggests that AVP-D may be present. Dynamic stimulation of copeptin reserve with a hypertonic saline test is the most accurate assessment, with arginine stimulation being less reliable test but easier to perform (see Endotext chapter entitled “Diagnostic Testing for Diabetes Insipidus”).

The water deprivation test is an indirect assessment of the AVP axis, measuring renal concentrating capacity in response to dehydration. It can be followed by assessment of renal response to the synthetic AVP analogue DDAVP, to determine whether any defect identified in urine concentrating ability can be corrected with AVP-replacement.

Water deprivation test results may be indeterminate. If AVP-D is suspected but diagnostic tests are inconclusive, a reasonable approach is a therapeutic trial of 10-20 mcg intranasal DDAVP per day with close monitoring of plasma Na + . Patients with AVP-D note improved symptoms without significant dilutional hyponatremia. Confirmation of AVP-D should lead to further pituitary function testing and cranial MRI. MRI may reveal the absence of posterior pituitary bright spot on T1- weighted sequences (), or a pituitary mass. In the absence of a structural problem, the MRI should be repeated 12 months after presentation to exclude a slow growing mass lesion. AVP-R requires renal tract imaging and additional renal studies.

While the regulation of thirst and AVP are discrete, the close neuroanatomical relationship of the structures responsible for osmoregulation of both processes means that some structural, neurovascular, and neuro-developmental lesions are associated with combined defects. Absent or reduced thirst (adipsia) in association with AVP-D predisposes to hypernatremic dehydration. Diagnosis follows that outlined for AVP-D, with parallel assessment of thirst perception.

Mild forms of AVP-D may not require treatment. Significant polyuria and polydipsia are treated effectively with DDAVP in divide doses: nasal spray 5-100 mcg per day; tablets 100-1000 mcg/day; or parenterally 0.1-2.0 mcg/day. Hyponatremia from plasma dilution can be avoided by omitting treatment for a short period on a regular basis (e.g. one dose per week). AVP-R may respond to removal of the causal agent (such as correction of hypokalemia or cessation of Lithium). However, drug-induced AVP-R may persist. Symptoms may respond partly to high-dose DDAVP (e.g. 4 mcg i.m. bid.). Hydrochlorothiazide (25 mg/day) either alone or in combination with Ibuprofen (200 mg/day) may be of some help. Urine output should not be expected to normalize. The approach to Primary Polydipsia is reduction in fluid intake. DDAVP treatment must be avoided because of the risk of significant hyponatremia.

Patients with adipsic AVP-D require careful management. Absence of normal thirst perception and/or regulation means that they may continue to drink at low plasma osmolalities that would normally suppress fluid intake. The combination of an obligate antidiuresis produced by DDAVP treatment, together with the potential for spontaneous fluid intake in excess of that required for maintenance of plasma volume and normal plasma osmolality, means they are at risk of fluid overload and dilutional hyponatremia. The same group of patients are also at risk of dehydration and hypernatremia if total body water loss is higher than a spontaneous fluid intake that is, by definition, uncoupled from normal osmo-regulatory control. In patients with adipsic AVP-D, managing fluid balance to maintain normal plasma sodium is therefore challenging. One approach is to combine a fixed DDAVP-dependent antidiuresis (giving urine output of some 2 L/day) with a variable daily fluid intake that aims to maintain the patient’s body weight at that which is known to be associated with normal plasma volume and normal plasma sodium (the ‘target’ weight, see below). e.g. Fluid intake for given day (L) = 2 L (i.e. urine output from fixed dose DDAVP) - (weight on given day in kg - target weight in kg)

Following initiation of DDAVP, patients require review for dose titration. When stable, they can be seen annually to assess symptom control and to check plasma Na + levels to avoid over-treatment. Adipsic AVP-D requires meticulous follow-up in a specialist service.