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PART 2. CLINICAL PROBLEMS SECONDARY TO DEFECTS IN THE HYPOTHALAMO-POSTERIOR PITUITARY AXIS

Defects in the production or action of VP manifest as clinical problems in maintaining plasma sodium concentration and fluid balance, reflecting the key role of the hormone in these processes.

A further group of related clinical conditions reflect primary defects in thirst. In some cases, the two may coincide, reflecting the close anatomical and functional relationship of both processes.

There are no clinical consequences resulting from defects in OT production or action.

1. Diabetes Insipidus

1.1. Classification

Diabetes insipidus (DI) is characterized by production of dilute urine in excess of 3l/24 hours (>40 ml/kg/24 hours in adults, >100 ml/kg/24 hours in infants). DI arises through one of three mechanisms (Table 2).

• Deficiency of VP: hypothalamic diabetes insipidus (HDI).
• Renal resistance to the antidiuretic action of VP: nephrogenic diabetes insipidus (NDI).
• Inappropriate, excessive water drinking: dipsogenic diabetes insipidus (DDI).
  

1.2. Hypothalamic Diabetes Insipidus (HDI)

HDI (also known as neurogenic, central, or cranial DI) is the result of deficient osmoregulated VP secretion. Plasma VP concentrations are inappropriately low with respect to prevailing plasma osmolalities. Presentation with HDI implies destruction or loss of function of more than 80% of vasopressinergic magnocellular neurons. It is rare (estimated prevalence of 1: 25000), with an equal gender distribution. Though persistent polyuria can lead to dehydration, most patients can maintain water balance through appropriate polydipsia if given free access to water.

1.2.1. Aetiology

Most cases of HDI are acquired. Trauma (head injury or surgery) can produce HDI through damage to the hypothalamus, pituitary stalk, or posterior pituitary. Pituitary stalk trauma may lead to a triphasic disturbance in water balance, an immediate polyuric phase followed within days by a more prolonged period (up to several weeks) of antidiuresis suggestive of VP excess. This second phase can be followed by reversion to HDI, or recovery. This characteristic 'triple response' reflects initial axonal damage; the subsequent unregulated release of large amounts of pre-synthesized VP; and either recovery or development of permanent HDI (as determined by the magnitude of initial damage to vasopressinergic neurons). The initial polyuric phase is associated with the presence of circulating inhibitors of VP action, which may be partly processed VP precursors (16). All phases of the response are not apparent in all cases.

Hypothalamic tumours or pituitary metastases (e.g. breast or bronchus) can present with HDI. However, primary pituitary tumours rarely cause HDI. In childhood, craniopharyngioma and germinoma/teratoma, are a relatively common cause (17) (Figure 8). HDI can present in pregnancy: placental vasopressinase activity decompensating previously antidiuretic capacity through increased VP degradation. Polyuria and polydipsia often revert to normal after delivery. Permanent HDI may develop if the natural history of the defect is progressive.

Figure 8. Sagital MRI of suprasellar cystic craniopharyngioma in a child presenting with hypothalamic diabetes insipidus. The child presented with a 2-month history of polyuria and polydipsia. Treatment was with cyst decompression and sub-total surgical excision.

Familial forms account for 5% of HDI. The Wolfram, or DIDMOAD syndrome (Diabetes Insipidus, Diabetes Mellitus, Optic Atrophy, and Deafness) is a rare, recessive multi-component disorder. It has several phenotypic features in common with mitochondrial (mt) cytopathies, though no specific mt gene mutation has been confirmed in this disorder. It is proposed that both mt and autosomal genes contribute to the pathogenesis (18, 19).

Autosomal dominant familial HDI is caused by loss of function mutations in exons 1 and 2 of the VP gene (Figure 9). It typically presents in childhood, though the age of presentation varies considerably, reflecting variation in the progressive loss of VP secretion. Growth retardation may be an early sign (20). Mutant VP precursors accumulate in the endoplasmic reticulum of vasopressinergic neurons, to which they are neurotoxic; the basis of both the progressive loss of VP release, and the dominant inheritance (21, 22). Spontaneous remission of symptoms has been reported in middle age. The mechanism of this phenomenon is unclear. As VP secretion does not recover, both increased renal sensitivity to residual VP secretion and VP-independent AQP2 expression have been proposed.

Figure 9. Schematic diagram of the Vasopressin-neurophysin II gene and its product, showing the location and type of mutations identified in autosomal dominant familial hypothalamic diabetes insipidus. Though mutations have been described in all three exons, and involve all parts of the VP-NPII precursor except the co-peptin moiety, the majority occur in exons 1or 2.

1.22. Investigation

The aim of investigation is outlined below.

• To confirm DI.
• To classify the DI: HDI, NDI or DDI.
• To establish the aetiology of the specific form of DI.

After establishing polyuria (and thus DI), and excluding hyperglycaemia, hypokalaemia, hypercalcaemia and significant renal insufficiency, attention should be focused on the VP axis.

Direct measurement of plasma VP in response to osmotic stimulation differentiates HDI from other causes of polyuria. However, access to reliable VP assays has been limited. A test using a surrogate endpoint of VP release has thus been developed, assessing the capacity to concentrate urine during the osmotic stress of controlled water deprivation (the water deprivation test). Renal sensitivity to exogenous VP can be determined as part of the test (Table 3). Diagnostic interpretation is as follows.

• HDI: urine osmolality less than 300mOsm/kg accompanied by plasma osmolality greater than 290 mOsm/kg after dehydration; urine osmolality should rise above 750 mOsm/kg after desmopressin (DDAVP).
• NDI: failure to increase urine osmolality above 300 mOsm/kg after dehydration, with no response to DDAVP.
• DDI: appropriate urine concentration during dehydration, without significant rise in plasma osmolality.

In practice, the test is often indeterminate for a number of reasons.

• Incomplete defects or mild forms of DI: many presentations are incomplete or mild. Water deprivation testing in such cases can give results that appear normal.
• Secondary partial NDI: dissipation of the intra-renal medullary concentration gradient due to prolonged polyuria (independent of aetiology) can produce partial NDI. This can make interpretation of the water deprivation test difficult.

Differentiation of HDI from other forms of DI can be made by direct measurement of plasma VP during the controlled osmotic stress of a hypertonic 5% - sodium chloride infusion (23). Patients with HDI have undetectable VP levels during the progressive hyperosmolar stress, or values falling to the right of the normogram relating plasma VP to plasma osmolality (Figure 10). In NDI, plasma VP is inappropriately high for the prevailing osmolality, consistent with VP resistance. In DDI, the relationship of plasma VP to plasma osmolality is normal. Parallel assessment of the thirst response to hyperosmolar stress may show inappropriate thirst perception in this situation. Hypertonic stress testing is not interpretable if it produces significant nausea, as this acts as a powerful non-osmotic stimulus of VP release.

Figure 10. The relationship of plasma VP concentration to changes in plasma osmolality during controlled hypertonic stimulation in diabetes insipidus. Measurement of plasma VP during controlled hypertonic stress testing can effectively differentiate between HDI, NDI and DDI.

A pragmatic alternative to VP measurements during hypertonic stress, in situations where a water deprivation test has proved non-diagnostic, is a controlled therapeutic trial of DDAVP: 10-20mcg of intra-nasal DDAVP per day for 2-4 weeks, with monitoring of plasma sodium every 2-3 days. Patients with DDI exhibit progressive dilutional hyponatraemia, whereas those with NDI remain unaffected. Patients with HDI experience improvement in polyuria and polydipsia, but remain normonatraemic. Measurement of urinary VP concentration during a water deprivation test may be an additional alternative to direct measurement of plasma VP during graded hypertonic stress (24).

In HDI, imaging of the hypothalamus, pituitary and surrounding structures with MRI is essential to exclude mass lesions. Idiopathic and familial HDI are associated with loss of the normal hyperintense signal of the posterior pituitary on T1-weighted images (Figure 11). Signal intensity is correlated strongly with VP content of the gland (25).

Figure 11. Loss of the posterior pituitary 'bright spot' on T1 weighted MRI in hypothalamic diabetes insipidus. The normal posterior pituitary can be demonstrated as a 'bright spot' within the sella turcica on T1-weighted MRI (a). This increased signal intensity can be lost in HDI (b). An ectopic posterior pituitary 'bright-spot' can be seen some cases of childhood onset hypopituitarism, implying failure to complete normal developmental migration. Function can be normal despite the aberrant positio

1.2.3. Treatment

The treatment of choice for those with significant symptoms is the synthetic, long-acting VP analogue DDAVP: intranasal spray (5-100 mcg daily); parenteral injection (0.1-2.0 mcg daily); or oral (100-1000 mcg daily), in divided doses. There is wide individual variation in the dose required to control symptoms. Dilutional hyponatraemia is the most serious potential adverse effect. This can be avoided by omitting treatment on a regular basis (perhaps weekly), to allow a short period of breakthrough polyuria and thirst. It is common for patients using oral DDAVP to experience intermittent breakthrough symptoms.

2. Nephrogenic Diabetes Insipidus (NDI)

NDI is due to renal resistance to the antidiuretic effects of VP. Primary familial forms are rare. X-linked recessive familial NDI is caused by inherited loss of function mutations of the V2-R. Over seventy different mutations have been described, affecting all aspects of receptor function: expression; ligand binding; and G-protein coupling. Most lead to complete loss of function, though a few are associated with a mild phenotype (26).

10% of kindreds with familial NDI have an autosomal recessive form, with normal V2-R function. Affected individuals harbour loss of function mutations of the AQP2 gene. Most mutations occur in the region coding for the transmembrane domain of the protein. Additional rare kindreds have been described harbouring a mutation in the portion of the gene encoding the carboxyl-terminal intracellular tail of AQP2. The NDI of these kindreds is inherited as an autosomal dominant trait, mutant protein sequestering the product of the wild type AQP2 allele within mixed tetramers in a dominant-negative manner (27).

More commonly, NDI is due to a variety of acquired metabolic or drug effects (Table 2). The final common pathway producing NDI in many of these cases is down-regulation of AQP2 expression. NDI secondary to lithium toxicity can persist after drug withdrawal, and can be irreversible.

Secondary/acquired cases of NDI are managed by removing the underlying cause, and ensuring adequate hydration. Additional measures can be used for persistent, severe symptoms. These rarely reduce urine volumes by more than 50%. High dose DDAVP (4 mcg im. bd) can produce a response in partial NDI, especially if the lesion is acquired. Additional treatment options, which can be used alone or in combination, include the following.

• Thiazide diuretics: hydrochlorothiazide 25 mg/24 hours. 
• Non-steroidal anti-inflammatory drugs: ibuprofen 200 mg/24 hours. 
• Low salt diets.

All probably work through reducing glomerular filtration rate, and reducing diluting capacity of the distal nephron.

3. Dipsogenic Diabetes Insipidus (DDI)

DDI is a polyuric syndrome secondary to excess fluid intake. Though structural abnormalities may be the cause, it is generally a manifestation of primary hyperdipsia, psychiatric disease, or secondary to drug effects. It can be associated with several abnormalities of thirst perception.

• A low osmotic threshold for thirst.
• An exaggerated thirst responses to osmotic challenge.
• An inability to suppress thirst at low osmolalities.

The structural and/or functional bases for these abnormalities have not been identified. The association of DDI with affective disorders is well recognized. Up to 20% of patients with chronic schizophrenia have polydipsia. Although this may reflect the primary thought disorder, abnormalities in osmoregulated VP release and thirst have been described (12). Whether these reflect long term effects of drug therapy, or primary defects in central processing, are unclear.

Though difficult, the treatment of DDI should address the underlying disorder. Switching to Clozapine may reduce polydipsia in those patients with refractory schizophrenia and a history of hyponatraemia on other dopamine antagonists. Individuals with persistent DDI are at risk of hyponatraemia if treated with DDAVP. Reduced fluid intake is the only rational treatment.