Diabetes insipidus

PITUITARY

Diabetes insipidus

Epidemiology All forms of diabetes insipidus are rare. HDI has an estimated prevalence of 1/25,000 and affects males and females equally. The prevalence of the other forms is unclear. Most cases present in adults, though familial HDI and NDI characteristically present in childhood.

Stephen Ball

Aetiology HDI – presentation with HDI implies loss of 80% of AVP production. Several pathological processes can be involved, all of which destroy magnocellular vasopressinergic neurons in the hypothalamus, or interrupt the transport or processing of AVP as it moves along the axons of these neurons for release at nerve terminals in the posterior pituitary (Figure 1). The condition can become worse in pregnancy as residual AVP is degraded by increased placental enzyme activity. Up to 50% of children and young adults with HDI have an underlying tumour or CNS malformation. Familial HDI comprises 5% of cases. NDI is most commonly caused by drug or metabolic effects (e.g. lithium toxicity, hypokalaemia, hypercalcaemia). Prolonged polyuria of any cause can result in partial NDI as a consequence of dissolution of the intrarenal solute gradient that facilitates renal water resorption. X-linked familial NDI results from loss-of-function mutations in the renal AVP receptor. The autosomal recessive form is caused by loss-of-function mutations in the AVP-dependent renal water channel aquaporin-2. DDI is associated with abnormalities in thirst perception: • low threshold for thirst • exaggerated thirst response to osmotic challenge • inability to suppress thirst at low plasma osmolalities. Structural lesions may be present, but neuroimaging is normal in most cases. DDI is associated with affective disorders.

Definition Diabetes insipidus is characterized by excess production of dilute urine – more than 40 ml/kg /24 hours in adults and more than 100 ml/kg/24 hours in children. It is divided into three subtypes: • hypothalamic diabetes insipidus (HDI) – relative or absolute lack of the posterior pituitary hormone vasopressin (AVP) • nephrogenic diabetes insipidus (NDI) – partial or total resistance to the renal antidiuretic effects of AVP • dipsogenic diabetes insipidus (DDI, primary polydipsia) – excessive, inappropriate fluid intake.

Stephen Ball is Senior Lecturer at the University of Newcastle upon Tyne and Consultant Physician at the Royal Victoria Infirmary, Newcastle upon Tyne, UK. He qualified from the University of London, and trained in medicine and endocrinology in London, Newcastle upon Tyne and Boston, USA. His research interests include cell replacement therapy and disorders of water balance, including diabetes insipidus. Conflicts of interest: none declared.

Aetiology of hypothalamic diabetes insipidus Primary

Genetic

Secondary/acquired

Developmental syndromes Idiopathic Trauma

DIDMOAD (Wolfram) syndrome, autosomal dominant, autosomal recessive Septo-optic dysplasia Lawrence–Moon–Biedel syndrome

Tumour Inflammatory

Vascular Pregnancy (associated with vasopressinase)

Head injury, post-surgery (transcranial, trans-sphenoidal) Craniopharyngioma, germinoma, metastases, pituitary macroadenoma Sarcoidosis, histiocytosis, meningitis, encephalitis, infundibuloneurohypophysitis, Guillain–Barré syndrome, autoimmune Aneurysm, infarction

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PITUITARY

Diagnosis and classification of diabetes insipidus by measurement of plasma vasopressin in response to graded hyperosmolar stimulation Plasma vasopressin (pmol/litre)

20 15

Nephrogenic Dipsogenic Hypothalamic

10 5 0

280

290

300

310

320

Plasma osmolality (mOsmol/kg) The shaded area depicts the normal-range response of plasma vasopressin as plasma osmolality is raised. Patients with hypothalamic diabetes insipidus have a response below the normal range. Those with dipsogenic diabetes insipidus have a normal response. Patients with nephrogenic diabetes insipidus have a response at the top of the reference range but coincident urine osmolalities that are dilute, consistent with vasopressin resistance.

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azide diuretics and non-steroidal anti-inflammatory drugs may act synergistically through reducing the glomerular filtration rate. The only rational approach to DDI is reduction in fluid intake. DDAVP treatment must be avoided in DDI, because of the risk of hyponatraemia. Follow-up – following initiation of DDAVP, patients may require frequent review by an endocrine service for dose titration. Thereafter, they can be seen annually to assess symptom control and to check plasma sodium levels to avoid over-treatment. Rarely, HDI occurs in combination with reduced thirst perception; this form of the condition requires meticulous follow-up in a specialist service.

Diagnosis and investigations Diabetes insipidus presents with polyuria and polydipsia. The history and examination may reveal features of systemic disease, associated endocrinopathy or a visual field or other neurological problem, or may raise the possibility of drug toxicity. Particular note should be taken of nocturia and night-time polydipsia, and polyuria must be distinguished from simple frequency without excess urine volume. The initial approach should be to confirm excess urine volume and exclude simple metabolic causes such as hyperglycaemia, hypercalcaemia and hypokalaemia. Definitive diagnosis requires referral to an endocrine service and testing of AVP production and action in response to osmolar stress. The water deprivation test measures renal concentrating capacity in response to dehydration and is an indirect measurement of the AVP axis. It is usually followed by assessment of renal response to the synthetic AVP analogue DDAVP. • In DDI, urine concentration is normal in response to dehydration. • In HDI, urine concentration fails in response to dehydration, but not to DDAVP. • In NDI, urine concentration fails in response to both manoeuvres. In practice, many results are indeterminate. Direct measurement of AVP production during graded hyperosmolar stimulation is the gold-standard method for diagnosing and classifying diabetes insipidus (Figure 2). Confirmation of HDI should lead to further investigation by pituitary function testing and cranial MRI. NDI requires renal tract imaging and consideration of renal biopsy if the defect persists.

Prognosis Isolated HDI has an excellent prognosis and patients should anticipate a normal quality of life. When HDI is associated with pituitary hormone deficiency, a tumour or systemic disease, the prognosis is dominated by the natural history of the specific aetiological process. NDI is difficult to treat, and the symptoms seldom respond completely. 

FURTHER READING Ball S G, Barber T, Baylis P H. Tests of posterior pituitary function. J Endocrinol Invest 2003; 26: (Suppl.): 15–24. Ball S G, Baylis P H. The neurohypophysis. In: Wass J A H, Shalet S M, eds. Oxford textbook of endocrinology and diabetes. Oxford: Oxford University Press, 2002: 87–99. Ball S G, Baylis P H. Normal and abnormal physiology of the hypothalamus and posterior pituitary. www.endotext.org

Management Mild forms of HDI may not require treatment. Significant polyuria and polydipsia are treated effectively with oral or intranasal DDAVP. High-dose DDAVP may be beneficial in partial NDI. Thi-

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