Diabetes insipidus and SIADH: Pathology review

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Case study0:00–0:51

Okay, so two people were admitted to the Endocrinology ward. One of them is 35 year old Imre, who came in with intense polyuria and polydipsia.
Imre was dehydrated and presented with dry mouth, headache, dry skin and dizziness. Several tests were done and results showed increased serum osmolality and further on, a desmopressin test was done.
During the test, an ADH analogue was administered and urine osmolality increased. The other person is 45 year old Sienna who came in to do some routine tests because she started taking cyclophosphamide and wanted to make sure that there are no complications.
Her lab results showed hyponatremia, decreased blood osmolality, and her urine osmolality was higher than serum osmolality.
Now, both individuals are unable to maintain normal osmolality. But to understand this we need to go over a bit of physiology first.

Physiology0:51–3:15

In the brain, specifically in the hypothalamus, there are osmoreceptors which can sense the osmolality of the blood, or how concentrated it is.
Osmolality is the concentration of dissolved particles in the blood plasma, or the liquid portion of blood. There are a number of dissolved particles in the blood plasma, but the major ones are glucose, sodium, and blood urea nitrogen, and a normal osmolality is between 285 and 295 milliOsmoles per kilogram.
Now, during periods of dehydration there is an increase in concentration of these particles in the blood and osmolality increases.
The osmoreceptors in the hypothalamus sense the change in osmolality and this triggers the sensation of thirst. The water that we drink gets absorbed and dilutes the blood, bringing the osmolality back to normal.
In addition to osmoreceptors, the hypothalamus also contains the supraoptic and paraventricular nuclei that produce antidiuretic hormone, or ADH, which is then sent to the posterior pituitary for storage.
ADH is also called vasopressin because it causes smooth muscle around the blood vessels to contract, which increases resistance and raises blood pressure.When the osmoreceptors detect high osmolality, they signal the supraoptic nucleus to send ADH into the blood which travels to the kidneys, specifically to the principal cells in the distal convoluted tubule, and collecting ducts, of the nephrons.
Here ADH binds to a receptor called vasopressin receptor 2, or VR2. This causes aquaporin proteins inside the principal cells to embed into the cell membrane and open a channel that only lets water from the lumen of the nephron back into the blood.
Just like drinking more water, this dilutes the blood, and returns plasma osmolality to a normal level. However, this reabsorption process also decides how much water leaves the body as urine, and how concentrated the urine is, which is one of the things that keeps a normal urine osmolality between 300 and 900 milliOsmoles per kilogram.

Diabetes insipidus3:15–3:47

Now that we know all this, diabetes insipidus is when the kidneys reabsorb too little water, so the water remains in the nephrons and is lost via urine.
This leads to a lot of dilute urine, or polyuria. Since there’s less water in the blood, plasma osmolality increases and that triggers thirst and polydipsia.
Now, if the problem is caused by a lack of ADH, it’s called central diabetes insipidus. If it’s due to a decreased response to ADH by the kidneys, it’s called nephrogenic diabetes.

Central diabetes insipidus3:47–4:29

Let’s start with central diabetes insipidus, which can be caused by conditions that affect the hypothalamus, in which case it won’t be able to produce ADH, or conditions that affect the pituitary gland, in which case there’s no place to store the ADH, and in some cases, both the hypothalamus and the pituitary gland are affected.
As a result, there’s insufficient ADH in the blood, and that means there is less vasoconstriction, and insufficient aquaporins in the distal convoluted tubule and collecting duct.
Some causes of central diabetes insipidus include pituitary tumors, head trauma, head surgery, ischemic encephalopathy, autoimmune conditions or sometimes, the cause can be idiopathic.
Then there’s nephrogenic diabetes insipidus, which is when there’s a problem with the kidneys themselves, which makes them unresponsive to ADH.

Nephrogenic diabetes insipidus4:29–5:25

A high yield fact is that this is often due to a hereditary genetic defect of the vasopressin receptors or aquaporin proteins.
Both of these lead to nephrons that are unresponsive to ADH. In addition, there are medications like lithium that can decrease the production of aquaporin proteins in the collecting duct.
Sometimes, nephrogenic diabetes insipidus can be caused by hypokalemia. That’s because the aquaporins can degrade in the early phases of hypokalemia.
Sometimes nephrogenic diabetes can also be secondary to hypercalcemia, through an unclear mechanism. Finally, demeclocycline, which is an ADH antagonist, can block the vasopressin receptors, leading to nephrogenic diabetes insipidus.
Now, the symptoms of both central and nephrogenic diabetes insipidus are polyuria and polydipsia and you have to remember this for your tests.

Symptoms5:25–5:52

A person with diabetes insipidus typically produces over 3 liters of dilute urine each day, so it can quickly lead to dehydration and hypotension.
The increase in plasma osmolality can result in fatigue, nausea, poor concentration, or confusion.The diagnosis of diabetes insipidus starts with a blood osmolality test, which would show an increased blood osmolality of above 290 milliosmoles per kilogram in both central and nephrogenic diabetes insipidus.

Diagnosis5:52–8:07

The urine specific gravity is lower than 1006, meaning the kidneys aren’t able to properly concentrate urine. There’s also hyperosmotic volume contraction This means that there’s decreased extracellular fluid in the body, and the remaining fluid is hyperosmotic since the water is lost, but the solutes remain.
Okay, the way to differentiate central and nephrogenic diabetes insipidus is to look at the ADH level; with central diabetes insipidus, there’s low ADH, while with nephrogenic diabetes insipidus, ADH is normal or high.
Remember this as it’s a very high yield concept. In addition, a water deprivation test can be done to distinguish diabetes insipidus from psychogenic polydipsia, which is when an individual drinks more water than they need, because of a variety of psychological or psychiatric causes.
That’s where an individual doesn’t drink water for 2 to 3 hours, then hourly measurements of urine volume and osmolality are done.
In a person with diabetes insipidus, urine osmolality will normally stay below 300 mOsm/kg despite having no fluid intake.
With psychogenic polydipsia, urine osmolality increases during the test. If diabetes insipidus is confirmed, the second step is to administer an ADH analog like desmopressin, which is a medication that works like ADH.
If urine osmolality increases about 50 percent from the baseline value, and remember this number for your exams, that suggests that the kidneys are responsive to ADH.
This means the cause is probably central diabetes insipidus, meaning it's due to low levels of ADH. If the ADH analog causes urine osmolality to increase only slightly, then the kidneys are not responding to the ADH properly, meaning that it’s nephrogenic diabetes insipidus.Treatment of central diabetes insipidus relies on desmopressin and proper hydration.

Treatment8:07–8:52

Treatment of nephrogenic diabetes insipidus relies on thiazide-like diuretics, like hydrochlorothiazide which are given to increase urine excretion of sodium.
Since sodium contributes to blood osmolality, getting rid of sodium reduces blood osmolality and stops the hypothalamus from triggering thirst.
Other options include a potassium-sparing diuretic like amiloride and this can be used together with thiazide diuretics.
Besides diuretic, other options include indomethacin and dietary measures, like hydration, dietary salt restriction and avoidance of medications that can harm the kidneys, like aminoglycosides, for example.
Now, we’ll be moving on to talk about the syndrome of inappropriate antidiuretic hormone secretion or SIADH for short. SIADH is a condition where the body makes way too much ADH, as opposed to diabetes insipidus, where there isn’t any ADH or where the kidney doesn’t respond to ADH.

SIADH8:52–12:31

Okay, SIADH can be caused by several conditions. One of them is ectopic ADH secretion from a tumor outside the hypothalamus or pituitary.
This is called paraneoplastic syndrome and it can be associated with small cell lung carcinoma. Other causes include central nervous system surgery or head trauma that can cause ADH to be released from the damaged pituitary gland.
Pulmonary diseases such as pneumonia and chronic obstructive pulmonary disease or COPD can lead to SIADH but the exact mechanism is unknown.
Finally, SIADH can be caused by medications like cyclophosphamide, which increases the number of ADH receptors on principal cells.
Now, with SIADH, the increased ADH leads to increased water reabsorption in the kidneys. Water retention leads to an expansion of the extracellular fluid.
Some of this water will move into the intracellular fluid. However, there will be a lot of water left in the extracellular fluid, leading to volume expansion.
Increased water in the extracellular fluid leads to dilutional hyponatremia, meaning the total sodium level is actually normal, but the sodium is distributed into a larger volume of water.
This causes a particular type of hyponatremia called euvolemic hyponatremia and since it’s euvolemic, there’s no edema on clinical examination.
Volume expansion also increases blood volume and pressure, causing the heart to release. Atrial natriuretic peptide or ANP, and brain natriuretic peptide or BNP.
And yes, I know what you’re thinking - but despite its name, BNP is also released by the heart!. Both will dilate the blood vessels to decrease blood pressure and they also increase glomerular filtration rate.
The result is more water and sodium are filtered out and excreted via urine. Next, increased blood flow to the kidneys will reduce renin release which means there’s decreased angiotensin II and aldosterone.
Aldosterone normally acts on the distal convoluted tubule and collecting ducts to increase sodium and water reabsorption, so when this hormone is low, we are getting rid of more water, but also even more sodium through the urine.
Now, if there’s severe hyponatremia, more water will move inside cells due to osmosis. The most dangerous complication of this is cerebral edema and seizures.
For diagnosis, remember that people with SIADH will have a hyponatremia, decreased serum osmolality and increased urine osmolality.
For treatment, the first step is fluid restriction, and this is very high yield. After that, salt tablets, and IV hypertonic saline can help correct hyponatremia.
Diuretics to excrete the extra water and medications that antagonize the vasopressin receptor, such as tolvaptan, conivaptan and demeclocycline are also given.
Now, keep in mind that hyponatremia should be corrected slowly in order to prevent osmotic demyelination syndrome with severe neurological consequences.
All right, as a quick recap, Diabetes insipidus can be central, in which case there’s a problem in the hypothalamus or pituitary gland resulting in decreased ADH production or release.

Review12:31–13:46

Diabetes insipidus can also be nephrogenic, in which case there’s a problem with the kidneys themselves, and they are unresponsive to ADH.
Symptoms of both central and nephrogenic diabetes insipidus include polyuria and polydipsia. The diagnosis of diabetes insipidus is based blood osmolality over 290 milliosmoles per kilogram in both central and nephrogenic diabetes insipidus.
The urine specific gravity is lower than 1006 and there’s also hyperosmotic volume contraction. With central diabetes insipidus, there’s low ADH, while with nephrogenic diabetes insipidus, ADH is normal or high.
During a desmopressin test, a large increase in urine osmolality means there’s central diabetes insipidus and a small increase means there’s nephrogenic diabetes insipidus.
With SIADH there’s excess production of ADH, euvolemic hyponatremia, excessive free water retention which causes concentrated urine, and decreased serum osmolality.Now, back to our cases.

Summary13:46–14:45

Imre came in with intense polyuria and polydipsia and tests showed increased serum osmolality and a desmopressin test was done during which urine osmolality increased when an ADH analogue was given.
ADH levels were also done and they were low. Based on symptoms and test results, we can diagnose Imre with central diabetes insipidus, in which case treatment involves desmopressin and hydration.
Further investigations need to be done in order to find the cause. Sienna came in for routine tests, because she’s taking cyclophosphamide.
Her tests showed hyponatremia, decreased blood osmolality and increased urine osmolality, and all 3 are found in SIADH. The likely cause is her medication which increases the number of ADH receptors in the kidneys.
Treatment involves fluid restriction and salt tablets.
Diabetes insipidus and SIADH: Video and Causes | Osmosis