In the body, about 85% of the phosphate is stored in the bones, where it combines with calcium to make a tough compound called hydroxyapatite which is the stuff that makes bones hard. Of the remaining phosphate, a tiny amount is extracellular, or outside cells like in the blood, so this is the bit that gets measured, and the majority is intracellular, or inside cells, where it does all sorts of things.
It’s responsible for phosphorylation, where it binds to fats and proteins. It forms the high energy bonds of adenosine triphosphate or ATP, which is the most common energy currency in the cell. It’s part of the DNA and RNA backbonethat links individual nucleotides together, and is also part ofcellular signaling molecules like cyclic-adenosine monophosphate or cAMP. Bottom line - phosphate is super important.
Because most of phosphate is locked up with calcium in the bones, the levels of phosphate are heavily tied with the levels of ionized calcium in the body. If calcium levels fall, the fourparathyroid glands buried within the thyroid gland releaseparathyroid hormone which frees up both calcium and phosphate ions from the bones.
It does this by stimulating osteoclasts, the cells that break bone down, to release hydrogen ions which dissolves the hard,mineralized hydroxyapatite. As soon as the positively-charged calcium and negatively-charged phosphate are released from the bones, they grab onto each other again like a pair of star-crossed lovers, meaning that the ionized calcium level doesn’t really go up very much at all.
Now, these two make their way to the nephron of the kidney, and at this point in the proximal convoluted tubule, phosphate usually gets reabsorbed back into the blood via sodium-phosphate cotransporters.
It turns out, though, that parathyroid hormone also shuts this down. This means that phosphate is left in the lumen and eventually gets sent out in the urine. Now, that calcium’s still in the lumen, though, but parathyroid hormone also affects thedistal convoluted tubule and increases calcium reabsorption.
So when the dust settles, as a result of parathyroid hormone, phosphate is lost in the urine while ionized calcium is kept in the blood, so ionized calcium levels rise and phosphate levels fall!
With all of this in mind, hypophosphatemia can develop a few different ways. The first possibility is by having excess losses of phosphate. This can result in conditions like primary hyperparathyroidism which result in too much parathyroid hormone, which leads to excess phosphate being excreted in the urine.
Another example is Fanconi syndrome, which is where the proximal convoluted tubule essentially loses its capacity toreabsorb a variety of solutes - including phosphate, once again letting it get excreted in the urine.
Another possibility is not absorbing enough through the gastrointestinal tract, because usually phosphate ions are absorbed in the GI tract, but some substances like alcohol or a medication can impair that phosphate absorption, which means it gets excreted. This includes antacids that contain aluminum, calcium, or magnesium, all of which are positive ions that can bind with the negatively charged phosphate and block absorption.
Alternatively, a person may simply not be getting enough phosphate in the diet, although this is unusual because it’s found in nearly all foods. The exception is someone that’sstarving and severely malnourished, or someone who is actively depriving themselves of food, like in anorexia nervosa. In both of these situations, blood glucose levels are low and as a result cellular metabolism slows down considerably.
When an individual in this state starts to suddenly eat healthy meals again, like in a hospital setting, then they all the sudden get a bunch of glucose in their blood, and in response insulin usually skyrockets in order to push that new found glucose into the cells.
This causes a demand for phosphate in cells because the first step in glucose metabolism is to have the enzyme hexokinaseattach phosphate to the glucose. Also, production of ATP molecules themselves requires a lot of phosphate.
Now, this means that phosphate gets extracted from the blood, which causes phosphate levels, which have remained relatively normal until this point, to plummet. This is called refeeding syndrome, and it can cause levels of other electrolytes to rapidly change as well, putting these people at serious risk of developing cardiac arrhythmias and neurologic problems.
Similarly in diabetes, individuals can’t make enough insulin, so the cells are effectively “starving” even though they are surrounded by glucose in the blood. Sometimes these individuals can develop diabetic ketoacidosis, and to treat that complication, individuals are given insulin, and just like before, insulin causes the cells to extract glucose and phosphate from the blood, and the blood phosphate levels can fall quickly.
A final cause of hypophosphatemia is respiratory alkalosisbecause it causes extracellular CO2 levels to decrease as it gets ventilated out of the lungs. This causes intracellular carbon dioxide to freely diffuse out of the cell, raising the cellular pH which stimulates glycolysis, a metabolic process that requires a lot of phosphate. Similar to the process in refeeding syndrome, when cells need phosphate, they simply pull it out of the blood, causing hypophosphatemia.
Most people with mild hypophosphatemia have no symptoms, but severe hypophosphatemia can cause muscle weakness, weak bones or osteomalacia, and rhabdomyolysis which is a type of kidney damage due to muscle breakdown, as well as an altered mental status. In addition, hypophosphatemia, that occurs due to primary hyperparathyroidism, may show symptoms caused by the associated hypercalcemia.
A common mnemonic to remember these symptoms is “stones, thrones, bones, groans, and psychiatric overtones.”Stones is for calcium-based kidney stones or gallstones that can form, thrones refers to the toilet to remind you of thepolyuria or frequent urination that results from impaired sodium and water reabsorption. Bones is for bone pain that results after chronic hormone-driven demineralization in order to release calcium. Groans is for constipation and muscle weakness, both of which are partly due to decreased muscle contractions. Finally, psychiatric overtones refers to symptoms like a depressed mood and confusion.
Diagnosis of hypophosphatemia is based on the phosphate level being below 2.5 mg/dL, and treatment involves giving intravenous or oral phosphate and close monitoring of blood levels. In cases of malnutrition, it’s important to gradually increase caloric intake and supplements over several days to avoid refeeding syndrome.
Alright, as a quick recap, hypophosphatemia describes a blood phosphate level below 2.5 mg/dL, which can result fromincreased excretion, decreased absorption and intake, or a shift of phosphate from the bloodstream to the inside of cells. Regardless of the cause, the treatment is typically a slow increase in phosphate levels to bring them back to normal once again