AssessmentsDiabetes insipidus and SIADH: Pathology review
USMLE® Step 1 style questions USMLE
A 65-year-old man is brought to the emergency department because of nausea, vomiting, muscle weakness, and confusion. The symptoms began two days ago. Review of his medical record reveals that he has a recent diagnosis of depression for which fluoxetine therapy was initiated four-weeks ago by his psychiatrist. Temperature is 37.2°C (99°F), pulse is 78/min, and respiratory rate is 15/min and blood pressure is 117/78 mmHg. On physical examination, the patient has difficulty standing due to generalized weakness. Laboratory studies are as follows:
|Blood Urea Nitrogen||15 mg/dL|
|Serum Osmolarity||241 mOsm/kg|
|Urine Osmolality||405 mOsm/kg|
Which of the following is the next best step in management?
Content Reviewers:Yifan Xiao, MD
Okay, so on the Endocrinology ward, two people came in.
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 water deprivation 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. 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.
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.
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.
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.
Then there’s nephrogenic diabetes insipidus, which is when there’s a problem with the kidneys themselves, which makes them unresponsive to ADH.
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.
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.
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.
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.
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.
After taking an ADH analog like desmopressin, which is a medication that works like ADH, the urine osmolality might increase about 50 percent from the baseline value, and remember this for your exams.
- "Robbins Basic Pathology" Elsevier (2017)
- "Harrison's Principles of Internal Medicine, Twentieth Edition (Vol.1 & Vol.2)" McGraw-Hill Education / Medical (2018)
- "" Reviews in Endocrine and Metabolic Disorders (2003)
- "Treatment of Lithium-Induced Diabetes Insipidus with Amiloride" Pharmacotherapy (2003)
- "Paraneoplastic Syndromes: An Approach to Diagnosis and Treatment" Mayo Clinic Proceedings (2010)
- "Syndrome of Inappropriate Antidiuretic Hormone Secretion Induced by a Single Dose of Oral Cyclophosphamide" Annals of Pharmacotherapy (2012)