USMLE® Step 1 style questions USMLE
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A 25-year-old woman presents to her family physician with polydipsia, polyuria, and dehydration. The excessive thirst began shortly after a car accident approximately three years earlier, which resulted in significant blood loss from the head. A routine blood chemistry reveals a serum sodium concentration of 144 mg/dL. If the physician orders a water deprivation test, which of the following laboratory results would most likely confirm a diagnosis of central diabetes insipidus?
With diabetes insipidus, “diabetes” means an increased passing of urine, and “insipidus” means tasteless; so diabetes insipidus is a condition characterized by the production of large quantities of dilute and tasteless urine.
The tasteless urine of diabetes insipidus distinguishes it from diabetes mellitus which describes sweet tasting urine- and, yes, urine was really tasted at one point in time to make that distinction!
Now, in the brain there’s a region called the hypothalamus.
Inside the hypothalamus 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 milli Osmoles per kilogram.
During periods of dehydration there is an increase in concentration of these particles in the blood and osmolality increases.
The osmoreceptors in the hypothalamus detect the increased osmolality and that triggers the sensation of thirst, which tells us to drink more water. The water then gets absorbed and dilutes the blood, bringing the osmolality back to normal.
In addition to osmoreceptors, the hypothalamus also contains a cluster of neurons that are found in a specific spot called the supraoptic nucleus.
These neurons produce a hormone called antidiuretic hormone, or ADH. ADH is also called vasopressin because it causes smooth muscle around the blood vessels to contract, which increases blood resistance and raises blood pressure.
When the osmoreceptors detect high osmolality, they signal the supraoptic nucleus to send ADH down the supraoptico-hypophyseal tract, which runs through the infundibulum or pituitary stalk, and into the posterior pituitary gland, where it is then released into the blood.
ADH travels to the kidneys, specifically to the distal convoluted tubule and collecting ducts of the nephrons and binds to a receptor called vasopressin receptor 2, or AVPR2.
When AVPR2 is bound, proteins called aquaporins, which usually sit in vesicles inside the cells of the distal convoluted tubule and collecting ducts, start to embed themselves in the apical surface of the cells, which is the side facing the lumen of the tubule.
These aquaporins ultimately allow water -- and only water -- to travel out of the lumen of the tubule and into the cells lining the nephron, and ultimately 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 milli Osmoles per kilogram.
Diabetes insipidus is when the kidneys reabsorb too little water from the lumen of the tubule, causing the body to produce unusually large quantities of urine, which is called polyuria.
Since there’s less water in the blood, plasma osmolality increases and that triggers thirst and causes an individual to drink a lot, which is called polydipsia.
There are four types of diabetes insipidus, each with its own underlying cause.
The first type is central diabetes insipidus, which is when there’s a problem in the hypothalamus or pituitary gland preventing ADH production or release. As a result, there’s insufficient ADH in the blood, and that means there is less vasoconstriction, and that there are insufficient aquaporins in the kidneys.
Central diabetes insipidus is often caused by damage to the hypothalamus osmoreceptors, the supraoptic nucleus, or the supraoptico-hypophysial tract, but in other cases, the exact cause is hard to identify.
The second type is nephrogenic diabetes insipidus, which is when there’s a problem with the kidneys themselves, which makes them unresponsive to ADH. That can happen due to a genetic defect which can lead to abnormal vasopressin receptors or aquaporin proteins that are unresponsive to ADH.
In addition, there are medications like lithium that can decrease the production of aquaporin proteins in the collecting duct.
Finally, there are kidney disorders like polycystic kidney disease that can cause diabetes insipidus.
The third type is gestational diabetes insipidus, which occurs when the placenta of a pregnant woman releases an enzyme called vasopressinase that breaks down vasopressin or ADH. As a result, ADH might still be produced and released as normal, but it doesn’t get to exert its full effect on the blood vessels or kidneys.
In women with gestational diabetes insipidus, vasopressinase is produced starting in week 8 of pregnancy, and peaks in the third trimester. As a result, the symptoms typically worsen during the course of the pregnancy right up until birth when the placenta is removed, but can continue for up to two months after birth due to residual vasopressinase.