Hypophosphatemia – causes, symptoms, diagnosis, treatment, pathology

Hypophosphatemia – causes, symptoms, diagnosis, treatment, pathology

November 5, 2019 35 By Jose Scott


Hypo- means under, phosphat- refers to phosphate,
and -emia refers to the blood, so hypophosphatemia means having a low phosphate level in the
blood, typically below 2.5mg/dL. Phosphate is made up of one central phosphorus
atom surrounded by four oxygen atoms in a tetrahedral arrangement, like a mini pyramid,
and has a charge of minus 3 and is written PO43-. 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 backbone that
links individual nucleotides together, and is also part of cellular 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 four parathyroid
glands buried within the thyroid gland release parathyroid 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 the distal 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 to reabsorb 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’s starving
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 hexokinase attach 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 causest he cells to extract glucose and phosphate from the blood, and
the blood phosphate levels can fall quickly. A final cause of hypophosphatemia is respiratory
alkalosis because it causes extracellular carbon dioxide 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 the polyuria
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 from increased 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. Thanks for watching, you
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