Diabetes insipidus

Diabetes insipidus is a disorder characterised by deficiencies in the production or response to anti-diuretic hormone (ADH). It results in the production of large quantities of dilute urine. It is a rare condition, affecting 1 in 25,000 approximately.

🏃‍♀️ Physiology

ADH, also known as arginine vasopressin (AVP) is produced in the hypothalamus, in the supraoptic and paraventricular nuclei. It is then transferred to the posterior pituitary gland (through neurohypophyseal capillaries). It is stored in the posterior pituitary until it is needed, when it is then released into the bloodstream.

The release of ADH is dependent on 2 factors:

1. Osmotic pressure - osmoreceptors located in the organum vasculosum of the lamina terminalis (OVLT) and the subfornical organ detect changes in osmolality of the blood. Generally speaking, the normal range for plasma osmolality is 280-295mOsm/kg. When the osmolality excedes this, ADH is secreted. When it falls below this, ADH secretion decreases.
2. Blood volume - baroreceptors within the left atrium, aortic arch and the carotid artery detect changes in arterial blood volume. Atrial natriuretic peptide (ANP) is released in response to atrial stretch. When ANP is released, it inhibits ADH release and also promotes natriuresis. ANP also inhibits the RAAS and also promotes vasodilation (all in an attempt to regulate the blood pressure). ADH does the opposite and responds in states of hypovolaemia. This is achieved through relay to the vagus nerve from the baroreceptors. The vagus nerve then stimulates the posterior pituitary to release ADH.

What does ADH do?

ADH has 3 main functions once it has joined the systemic circulation:

1. It promotes aquaporin 2 channels to be expressed on the walls of the collecting duct and distal convoluted tubule. This promotes water reabsorption and decreases urine output.
2. It acts on vascular smooth muscle to promote vasoconstriction.
3. It stimulates the release of adrenocorticotrophic hormone (ACTH) from the anterior pituitary.

🔢 Pathophysiology and classification

As mentioned earlier, diabetes inspidus occurs when there is a lack of ADH or lack of response to ADH. Accordingly, we can classify diabetes insipidus as such:

It can be classified as either:

• Nephrogenic diabetes insipidus
• Cranial diabetes insipidus

Nephrogenic diabetes insipidus

This is when the collecting ducts do not respond to ADH.

It may be acquired or inherited. Some factors that may cause it include:

• Drugs - lithium
• Genetics - X-linked recessive mutations of the AVPR2 gene, which codes for the ADH receptor, are most common. There is a less common mutation of the AQP2 gene which codes for the aquaporin channel. It is autosomal recessive.
• Intrinsic renal disease - such as pyelonephritis, sickle-cell, obstruction.
• Electrolyte imbalances - hypercalcaemia, hypokalaemia, hyperglycaemia.

Cranial diabetes insipidus

This is when the hypothalamus does not produce ADH for the posterior pituitary to secrete.

Most causes are idiopathic but other times it may be due to:

• Brain tumours - such as craniopharyngiomas or brain metastases.
• Brain surgery - especially on the pituitary in ases of adenomas.
• Head injury - such as subarachnoid haemorrhage.
• Pituitary ischaemia - such as in Sheehan syndrome or ischaemic strokes.
• Drugs - such as phenytoin or temozolomide.
• Radiotherapy
• Infiltrative disorders - such as sarcoidosis and haemochromatosis.

Other times it may be genetically acquired, such as in:

• Congenital malformations
• Wolfram syndrome - an autosomal-recessive, progressive, neurodegenerative disorder that results in diabetes mellitus, optic atrophy and varying levels of sensorineural deafness as well as central diabetes insipidus.
• ADH-neurophysiology gene mutations

😷 Presentation

• Polyuria - large volumes of dilute urine (>3 litres in 24 hours with an osmlality of <300mOsm/kg) are produced.
• Polydipsia (excessive thirst)
• Nocturia

Children may experience additional symptoms such as:

• Enuresis (involuntary urination)
• Failure to thrive

🔍 Investigations

🥇 Some first-line investigations we should do include:

• Serum electrolytes - hypernatraemia, hypercalcaemia, hypokalaemia and elevated urea nitrogen may be seen if there volume depletion.
• Blood glucose - should be normal. It should be done to exclude diabetes mellitus.
• 24-hour urine collection - to confirm polyuria. There should be >3 litres in 24 hours.
• ⭐️ Serum osmolality - should be elevated (>295mOsmol/kg)
• ⭐️ Urine osmolality - should be low.

💡 A combination of high serum osmolality and low urine osmolality strongly suggests diabetes insipidus.

• 🏆 To confirm a diagnosis, we need to perform a water deprivation test:

This is the historical method of confirming the diagnosis. It has 2 components, deprivation and then ADH stimulation:

1. Supervised water deprivation should yield an inability to concentrate the urine. This confirms that there is ADH dysfunction, however, at this point we are not able to distinguish if it is cranial or nephrogenic.
2. Synthetic ADH is provided and the urine osmolality is measured again a few hours later. If it is cranial (ADH production is not occurring but the kidneys are able to respond to ADH) then the osmolality will be high. If it is nephrogenic (the kidneys do not respond to ADH, whether it be endogenous or exogenous) the osmolality will remain low.

Diagnosis	Osmolality with deprivation	Osmolality after ADH
Cranial DI	Low	High
Nephrogenic DI	Low	Low
Primary polydipsia	High	High

🧰 Management