HDI (also known as neurogenic, central, or cranial DI) is due to deficient osmoregulated VP secretion. In most cases it is a partial defect, with patients having inappropriately low plasma VP concentrations with respect to concomitant plasma osmolalities. Presentation with HDI implies destruction or loss of function of more than 80% of vasopressinergic magnocellular neurones. Though persistent polyuria can lead to dehydration, given free access to water, most patients can maintain water balance through an intact thirst mechanism. HDI is rare, with an estimated prevalence of 1:25 000 and equal gender distribution.

Aetiology

 Most cases of HDI are acquired. Improvements in imaging and an appreciation of the varied presentation of inflammatory/ auto immune forms are responsible for fewer cases being designated idiopathic. Inherited/ familial forms account for 5% of HDI.

Trauma, either as a result of 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 polyuria characteristic of HDI followed within days by a more prolonged period of antidiuresis suggestive of VP excess. This second phase may last up to several weeks, and can be followed by reversion to HDI or recovery. Such a ‘triple response’ reflects initial magnocellular axonal damage; the subsequent unregulated release of large amounts of presynthesized VP; and ultimately, either recovery or development of permanent HDI, as determined by the degree of initial neuropraxia/ axonal shearing and damage. Not all phases of the response may be ap parent. Recent data suggest acute HDI can occur in up to 22% of non- selected patients presenting with traumatic brain injury (TBI), persisting in some 7% of the total TBI cohort on long- term follow- up.

Circulating antibodies to VP secreting neurons can be found in 30% of patients classified previously as having HDI with no identifiable cause, implying an autoimmune aetiology. Presence of anti- VP neurone antibodies in patients with HDI is associated with pituitary stalk thickening on magnetic resonance imaging (MRI). However, anti- VP neurone antibodies can also be found at low prevalence in patients with HDI secondary to histiocytosis X and following pituitary surgery, suggesting the specificity of the test or the auto- antibody response is low. Evidence of wider organ- specific autoimmunity common in isolated HDI.

Primary pituitary adenoma rarely causes HDI. Hypothalamic tumours, such as craniopharygioma and germinoma, are more common causes of HDI. Presentation with HDI can precede the radiological appearance of germinoma. Hypothalamic tumours and developmental defects such as septo- optic dysplasia (SOD) account for up to 50% of HDI in children. Hypothalamic or pituitary metastases (e.g. from primary breast or lung cancer) can present with HDI, as can primary brain malignancy and primary CNS lymphoma.

HDI can present in pregnancy. Placental vasopressinase activity can decompensate pre- existing limited antidiuretic capacity in patients with partial HDI through increased VP degradation that cannot be matched by increased hormone release. This can revert to normal after delivery, though permanent HDI may ultimately develop if the natural history of the central defect is progressive.

Wolfram Syndrome (WS)

Genetic studies have identified two subtypes of WS. WS1 is caused by loss of function mutations in the WFSI gene on Ch.4p16. WFSI encodes an 890 amino- acid glycoprotein, wolframin. Wolframin expression is restricted to the endoplasmic reticulum (ER) where it regulates ER stress and calcium homeostasis. Loss of function of wolframin triggers apoptosis and cell death. Non- inactivating mutations of WFSI are associated with autosomal dominant sensorineural hearing loss. WS1 may thus represent one extreme of a spectrum disorder.

WS2 is characterized by optic atrophy and diabetes mellitus. There are additional features of peptic ulcer disease and bleeding tendency which are not seen in WS1. WS2 is caused by loss of function mutations in the CISD2 gene. CISD2 encodes a protein expressed on both ER and the outer mitochondrial mem brane. Loss of function of CISD2 disrupts calcium flux between ER and mitochondria leading to autophagy and cell death in a manner similar to that seen in several other neurodegenerative diseases.

Autosomal Dominant Familial HDI

Autosomal dominant familial HDI is caused by mutations in the VP gene on chromosome 20. While it typically presents in childhood, the age of presentation varies considerably, reflecting variation in the progressive loss of VP secretion. A variety of different missense and nonsense mutations within exons 1, 2, and 3 of the VP gene have been identified in affected kindreds. Mutant VP precursors ac cumulate in the ER of magnocellular neurones, to which they are neurotoxic. This explains the both the progressive loss of VP release in the condition, the range of presentation and its dominant inheritance pattern: the product of a single mutated allele being sufficient to trigger neural degeneration. Growth failure may be an early clinical feature.

T he inherited HDI of the Brattleboro (BB) rat is due to a frame shift in exon 2 of the VP gene, resulting in a VP precursor with an altered carboxy terminus which also accumulates in the ER of vasopressinergic neurones. Interestingly, the HDI of the BB rat is inherited in a recessive manner, in contrast to the equivalent condition in man.

Investigation of Polyuric States

The strategy of investigation of DI is to confirm the polyuric state, define its basis, and to explore possible primary aetiologies. After establishing significant polyuria of greater than 3 l/ 24 h in adults and excluding hyperglycaemia, hypokalaemia, hypercalcaemia, and significant renal insufficiency, attention should be focused on the VP axis. Direct tests that measure plasma VP in response to osmotic stimulation would be the ideal modality to differentiate HDI from other causes of polyuria. However, access to reliable VP assays have been limited. Because of this, an indirect test using a surrogate endpoint of VP release (the ability of the kidney to produce concentrated urine during osmotic stress) has historically been used to differentiate the cause of confirmed polyuria: the water deprivation test.

Indirect Tests of the Hypothalamo- Neurohypophyseal (AVP) Axis: The Water Derivation Test

 The water deprivation test assesses the capacity to concentrate urine during the osmotic stress of controlled water deprivation. The period of water deprivation can be followed by evaluation of the antidiuretic response to exogenous VP: the aim being to confirm renal sensitivity to VP or establish renal resistance. A standard protocol is outlined in Box 1. HDI can be distinguished by urine osmolality less than 300 mOsml/ kg, accompanied by plasma osmolality greater than 290 mOsml/ kg after dehydration. Urine osmolality should rise above 750 mOsml/ kg after desmopressin (DDAVP), indicating normal renal responsiveness. In contrast, failure to increase urine osmolality above 300 mOsml/ kg after dehydration together with failure to respond to DDAVP is diagnostic of NDI. Patients with DDI should concentrate urine appropriately during dehydration, without significant rise in plasma osmolality.

Box1. Protocol for water deprivation/ desmopressin test

In reality however, many patients have incomplete defects and manifest mild or moderate forms of DI. Moreover, prolonged polyuria of any type can impair urine concentrating ability through dissipation of the medullary interstitial concentration gradient, resulting in a partial functional NDI. The water deprivation test can be a poor discriminator in these circumstances. The water deprivation test has been shown to support the correct diagnosis of underlying the polyuric state in some 70% of patients overall; and in only 41% of patients with underlying primary polydipsia.

Direct Tests Used in the Differential Diagnosis of DI: The Utility of Measuring VP and Copeptin

An accurate diagnosis of HDI can be made by direct measurement of plasma VP during the controlled osmotic stress of a hypertonic 5% sodium chloride infusion. Patients with HDI have either un detectable VP levels, or values falling to the right of the normogram relating plasma VP to plasma osmolality. In NDI, plasma VP is in appropriately high for the prevailing urine and plasma osmolality, indicating VP resistance. In DDI, the relationship of plasma VP to osmolality is normal. The test is not interpretable if the patient experiences nausea, a powerful non- osmotic stimulus of VP release, during the test. Importantly, access to reliable VP assays has been limited and there are significant preanalytic obstacles in the scaling of this test to wider use. The addition of VP measurements as an adjunct to the standard water deprivation test does not add value.

Copeptin, the c- terminal fragment of the VP- NP precursor is released in equimolar amounts to VP. In comparison to VP, the peptide is much more stable in plasma, making it an attractive alternative analyte to VP to support the differential diagnosis of poly uric states. Copeptin concentrations greater than 4.9 pmol/ L during osmotic stimulation with hypertonic fluid can reliably discriminate between HDI and primary polydipsia, with a diagnostic accuracy of 96%. As with VP, the addition of copeptin to the standard water deprivation test does not improve the diagnostic accuracy of the test.

Additional Tests to Support the Differential Diagnosis of Polyuric States

 A pragmatic alternative to VP measurements during hypertonic stress if there is diagnostic uncertainty following water deprivation is a controlled therapeutic trial of DDAVP: 10– 20 mcg of intranasal 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.

In familial autosomal dominant HDI, sequencing of the VP gene can help to establish the diagnosis in at- risk individuals early in the natural history of the disease and at a time when the water deprivation test can be equivocal.

Neuroimaging in HDI

Imaging of the hypothalamus, pituitary, and surrounding structures is essential in patients with HDI. MRI is the modality of choice. HDI is associated with the loss of the normal hyperintense signal of the posterior pituitary on T1- weighted images. Signal intensity is correlated strongly with VP content of the gland. As some hypothalamic germ cell tumours can be slow growing, imaging should be re peated after 6– 18 months if the initial scan shows no demonstrable lesion. A negative scan at this stage should be taken as reassuring in the absence of a change in clinical features. Importantly, the absence of a posterior pituitary bright spot on imaging is not specific and can occur in a range of physiological situations. The finding should therefore not be taken as diagnostic of HDI.

Treatment

Patients with a urine output of less than 4 l/ 24 h can be managed by advising adequate fluid intake. The treatment of choice for those with more severe symptoms is the synthetic, long- acting VP analogue DDAVP; given as an intranasal spray (5– 100 mcg daily), parenterally (0.1– 2.0 mcg daily), or orally (100– 1000 mcg daily) in divided doses. There is wide individual variation in the dose required to control symptoms. DDAVP has twice the antidiuretic potency of VP, but has minimal vasopressor activity. It is well tolerated. Dilutional hyponatraemia is the most serious potential ad verse effect. This can be avoided by omitting treatment on a regular basis (perhaps weekly), to allow a short period of breakthrough polyuria and thirst.

Acute onset of HDI following pituitary or neurosurgery is usually transient and may not require intervention. Hypernatraemia can develop if cognition is impaired or access to water limited. Polyuria should be managed with DDAVP (parenteral administration may be required). As the situation is dynamic, a single dose of DDAVP may be sufficient to manage the patient until normal posterior pituitary function returns. Additional doses can be administered if polyuria persists or recurs. Regular DDAVP may be used if symptoms persist beyond 48 hours.

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مواضيع ذات صلة

Syndrome of Inappropriate Antidiuresis

The Physiology of oxytocin (OT)

Regulation and Biological Actions of Growth Hormone and Prolactin

Hypothalamic Control of Growth Hormone Secretion

Corticotropin-Releasing Hormone

The Physiology of Vasopressin

Gonadotropin-Releasing Hormone

Thyrotropin-Releasing Hormone

Biosynthesis of Adrenal Cortex Mineralocorticoids, Glucocorticoids, and Some Androgens

Mechanisms of hormone action: Cell Signaling by Membrane Receptors

Biosynthesis of Peptide and Protein Hormones

Hormones and Their Communication Systems