Hyperphosphatemia

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Introduction0:00–0:19

With hyperphosphatemia, hyper- means over, -phosphat- refers to phosphate, and -emia refers to the blood, so hyperphosphatemia means having a high phosphate level in the blood, typically above 4.5 mg/dL.

Physiology0:19–2:57

Now, phosphate is made up of one central phosphorus atom surrounded by four oxygen atoms in a tetrahedral arrangement, kind of 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 the 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 it’s also part of cellular signaling molecules like cyclic-adenosine monophosphate or cAMP.
Bottom line is that phosphate is really important. Now, 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, meaning that the ionized calcium level doesn’t really go up very much at all.
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. So 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, 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!

Pathophysiology2:57–8:24

With all that in mind, hyperphosphatemia can develop a few different ways. The first possibility is as a result of acute or chronic kidney disease, and for this we’ll use some numbersss.
So, let’s say normally the glomerular filtration rate, or GFR, which is the fluid filtered into the kidney per unit time, is 180 L / day, and the phosphate concentration of that blood is 0.04 g / L, that means that 7.2 g of phosphate get filtered per day, and let’s say 90% of that gets reabsorbed, or 6.48 g, that leaves 10%, or 0.72 grams to get excreted per day.
Now with kidney disease, the GFR falls to 28.8 L/day, which means only 1.2 g gets filtered, and only 0.12 g get excreted in a day, and so where there was 0.72 grams being excreted per day, now there’s only 0.12 g, and that means that the difference stays in the blood every day, and this contributes to hyperphosphatemia!
This number, 28.8 L/day, or 20 mL/min, is the point at which it’s thought excretion can’t keep up with intake. In addition, the kidneys may be unable to reabsorb calcium and so more gets excreted.
Remember that in response to low calcium, the parathyroid glands release parathyroid hormone...but since calcium just gets wasted, it keeps releasing parathyroid hormone - this is called secondary hyperparathyroidism because the primary problem is with the kidneys.
This causes a continuous release of calcium and phosphate from the bones like an open tap, and while calcium is excreted due to impaired reabsorption, phosphate is reabsorbed due to impaired excretion, so phosphate ends up building up in the blood.
To make matters worse, all this loss from the bones makes them thin and weak, which is part of a process called renal osteodystrophy, which describes the overall bone changes that happen in people with chronic kidney disease.
Related to this is pseudohyporparathyroidism, which is where the kidneys simply don’t respond to parathyroid hormone because of a genetic defect in the parathyroid hormone receptor.
Since parathyroid hormone tells the kidneys to save calcium and get rid of phosphate, calcium again gets lost and phosphate builds up in the blood, following the same pattern as kidney disease, including the thinning of the bones.
All right, so since, again, parathyroid hormone causes excretion of phosphate and reabsorption of calcium, then another cause of hyperphosphatemia is hypoparathyroidism, when the parathyroid glands don’t produce enough parathyroid hormone in the first place.
This results in the same situation of increased reabsorption of phosphate and decreased reabsorption of calcium. This can happen following a thyroid gland removal surgery when the parathyroids are accidentally taken out too or radiation treatment for cancer of the head or neck.
Also, people with the genetic disease DiGeorge syndrome, are often born with parathyroid glands that are too small and can’t produce enough parathyroid hormone.
Alternatively, phosphate levels can rapidly increase in the blood from excessive intake and absorption through the gastrointestinal tract or bloodstream via intravenous fluids.
One cause is taking too much of a phosphate-based laxative either orally or rectally as an enema. A final cause of hyperphosphatemia relates to the fact that most phosphate in the body is within the cells.
Any time a lot of cells die, that phosphate gets spilled into the bloodstream, causing hyperphosphatemia. This includes things like crush injuries, like when a piano falls on someone’s legs, or tumor lysis syndrome, which is cancer treatment which causes lots of tumor cells to die all at once, or rhabdomyolysis, or rapid destruction of skeletal muscle cells.
Another situation is when living cells get affected by respiratory acidosis, which is when the carbon dioxide levels rise because a person isn’t breathing or ventilating it out of the lungs quickly enough.
That carbon dioxide can diffuse into a cell and react with water to form carbonic acid which quickly breaks into a proton and bicarbonate.
The bicarbonate goes back into the blood in exchange for a chloride ion, leaving behind a proton. And all this ends up lowering the cellular pH.
Now, normally glycolysis in the cell uses up a lot of phosphate, but this lower pH tends to inhibit glycolysis. So as a result, the cells don’t pull as much phosphate out of the blood, and this allows levels in the blood to rise.
Somewhat similarly, in diabetic ketoacidosis, there are low levels of insulin, and although the exact mechanism is unclear, it reduces the amount of phosphate that cells extract from the blood, causing it again to build up in the blood.
In this case, though, it’s a slower process since there’s also an osmotic diuresis or increased urination from the hyperglycemia, or high blood sugar.

Signs and symptoms8:24–9:53

Mild hyperphosphatemia doesn’t usually cause symptoms, but severe hyperphosphatemia can make neurons more excitable. This can trigger the spontaneous firing of neurons and tetany or the involuntary contraction of muscles.
This can end up causing Chvostek's sign, which is when facial muscles twitch after the facial nerve is lightly finger tapped 1 cm below the zygomatic process.
It can also cause Trousseau's sign, which is where a blood pressure cuff occludes the brachial artery, and that pressure on the nerve is enough to make it fire, resulting in a muscle spasm that makes the wrist and metacarpophalangeal joints flex.
It can also cause symptoms like tingling around the mouth, seizures, and bone pain. The high levels of phosphate also cause it to find and stick to calcium which forms bone-like crystals containing calcium and phosphate in places that they shouldn’t be, like just beneath the skin, in the walls of blood vessels, in the joints, or in the kidneys where they can form kidney stones.
With long-term hyperphosphatemia, the whole kidney can eventually turn into bone, which is called nephrocalcinosis. In other words, flesh literally turning to bone.
This widespread calcification of healthy tissues is called metastatic calcification. In this case, metastatic means that the tissue rapidly changes from one thing to another, rather than referring to cancer.

Diagnosis & Treatment9:53–10:46

Diagnosis of hyperphosphatemia is based on the phosphate level being above 4.5 mg/dL, and treatment involves decreasing phosphate intake.
And this is accomplished by avoiding foods that contain a lot of phosphate like dairy, meat, and soda - in other words, no more pepperoni pizza with coke.
To decrease the amount of phosphate that’s absorbed from the gastrointestinal tract, people can given medications called phosphate binders.
Now, you can also try to increase excretion of phosphate, and in people with healthy kidneys, a combination of intravenous saline and a loop diuretic like furosemide can increase excretion.
And this is called forced diuresis and it essentially overwhelms the proximal convoluted tubule of the nephron with so much fluid that it’s unable to effectively reabsorb solutes, including phosphate.

Review10:46–12:15

Alright, as a quick recap, hyperphosphatemia describes high phosphate levels in the blood, above 4.5 mg/dL, and this can result from increased absorption and intake, decreased excretion, or a shift of phosphate from the inside of cells to the bloodstream.
High levels of phosphate ions in the blood also like to bind with calcium forming bone like crystals which can slowly turn into bony structures.