CLINICAL RECOGNITION

Diabetes Insipidus (DI) is the excess production of dilute urine. Diagnosis requires a targeted history, examination and confirmation through appropriate laboratory and radiological investigations. DI presents with polyuria and polydipsia. Urine output is more than 40 ml/kg /24 hours in adults and more than 100 ml/kg/24 hours in children. DI reflects either the lack of production or action of the posterior pituitary hormone vasopressin (AVP). There are three subtypes.

• Cranial or hypothalamic DI (HDI): due to relative or absolute lack of AVP.
• Nephrogenic DI (NDI): due to partial or total resistance to the renal antidiuretic effects of AVP.
• Dipsogenic DI (DDI, primary polydipsia): where polyuria is secondary to excessive, inappropriate fluid intake.

All forms of DI are rare. HDI has an estimated prevalence of 1/25,000. While presentation is more common in adults, familial forms of both HDI and NDI characteristically present in childhood.

PATHOPHYSIOLOGY

The Physiology of AVP

AVP is a nine-amino acid peptide made within magnocellular neurones 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 (Figure 1).

Figure1.

The Neurohypophysis

AVP is produced from a large precursor that undergoes extensive post-translational processing (figure 2).

Figure 2.

Post-Translational Processing of Vasopressin

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 regulated in a parallel manner (Figure 3).

Figure 3.

The Physiological Regulation of AVP Production and Thirst by Plasma Osmolality

Nephrogenic DI

Renal resistance to AVP may reflect a toxic renal tubulopathy secondary to metabolic (e.g. hypokalemia; hypercalcemia) or drug effects (e.g. lithium). Prolonged polyuria of any cause can result in partial NDI through disruption of the intra-renal solute gradients and reduced tubular concentrating capacity.

X-linked familial NDI results from loss-of-function mutations in the renal AVP receptor (Figure 4). Autosomal recessive NDI is caused by loss-of-function mutations in the AVP-dependent renal water channel aquaporin-2.

Figure 4.

Loss of Function Mutations of the V2 Receptor in X-Linked Nephrogenic DI

DIAGNOSIS and DIFFERENTIAL

History and examination may reveal important clinical information

-Features of systemic disease

-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 (hyperglycaemia, hypercalcemia hypokalemia)

If polyuria is confirmed and simple causes are excluded, the clinician should proceed to a diagnostic Water Deprivation Test (Table 2)

Definitive diagnosis of DI requires testing of AVP production and action in response to osmolar stress. 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.

Further Investigations

Water deprivation test results may be indeterminate. If HDI is suspected but water deprivation test data 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 HDI note improved symptoms without significant dilutional hyponatremia. In the future, basal or stimulated measurement of copeptin may be the most useful investigation, when generally available.

Confirmation of HDI should lead to further pituitary function testing and cranial MRI. MRI may reveal the absence of posterior pituitary bright spot on T1- weighted sequences (Figure 5), or a pituitary mass. In the absence of structural problem, the MRI should be repeated 12 months after presentation to exclude slow growing mass lesion. NDI requires renal tract imaging and additional renal studies.

Figure 5.

MRI Appearance of the Posterior Pituitary in Hypothalamic/Cranial DI

TREATMENT

Mild forms of HDI 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).

NDI may respond to removal of the causal agent (such as correction of hypokalemia or cessation of Lithium). However, drug-induced NDI 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 normalise.

The approach to DDI is reduction in fluid intake. DDAVP treatment must be avoided because of the risk of significant hyponatremia.

Patients with adipsic DI 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 DI, 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)

FOLLOW-UP

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 DI requires meticulous follow-up in a specialist service.

GUIDELINE

1. Baldeweg SE, Ball S, Brooke A, Gleeson HK, Levy MJ, Prentice M, Wass J. In-patient management of Cranial Diabetes Insipidus. Endocrine Connections. 2018 [PMC free article: PMC6013691] [PubMed: 29930026]

REFERENCES

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