Hypercalcemia as a Paraneoplastic Syndrome

00:02 Hypercalcemia, the next paraneoplastic process we're going to discuss.

00:07 Hypercalcemia is the most common metabolic abnormality that occurs in malignancy.

00:13 In about 10% of malignancies, pretty high percentage, will have some degree of hypercalcemia.

00:19 This is mainly driven by the osteoclast being activated to resorb bone, and we'll talk about the mechanisms by which osteoclast will be activated in the setting of malignancy.

00:30 There is a endocrine process driven by parathyroid hormone-related protein, so this is not parathyroid hormone but it's a related protein that has many of the same effects as parathyroid hormone, and is elaborated by malignant cells.

00:46 There's also a paracrine effect, so if we activate in the bone, we have local inflammation, local tumor, we can release factors that will drive the activation of osteoblasts to cause osteoclast to resorb bone, and in particular, activating through the RANK ligand, that's the receptor activator of nuclear factor kappa-B ligand better say it just RANK ligand or inflammatory mediators such as Interleukin-1 tumor necrosis factor, transforming growth factor, all those can cause osteoblast activation, that will in turn, turn on the osteoclasts to resorb bone.

01:32 All this is going to be exacerbated by renal failure.

01:35 So if the kidneys are not able to effectively clear calcium, because there's been some damage, where you're going to be more prone to having hypercalcemia.

01:44 The symptoms are somewhat nonspecific.

01:47 In fact, many of you have probably memorized the stones, bones, groans and moans.

01:57 Those are kind of the manifestations of hypercalcemia.

01:59 So stones, you can get renal calculi due to calcium phosphate.

02:05 Bones, because we're resorbing from the bone.

02:08 Groans, you can have GI symptoms and moans are the neuropsychiatric effects.

02:14 So if you remember those, that's kind of how hypercalcemia manifestations.

02:19 And if the calcium level gets too high can result in coma and death.

02:25 So how is this happening? Kind of in a schematic here, we have tumor cells that are releasing that parathyroid hormone-related protein.

02:34 That hormone can act to grease to stimulate calcium reabsorption.

02:39 So normally, the kidney would be putting out excess calcium.

02:43 This stimulates the renal tubular epithelial cells to pull back more calcium, so the level goes up.

02:50 That hormone, the PTHrP also acts on osteoblasts sitting on the surface of bone and within their lacunae, and those in turn will make RANK ligand that will stimulate the resorption by osteoclast of bone to release more calcium.

03:09 So that will elevate the calcium levels as you see there.

03:12 And then finally, the effects of the stimulation of the osteoblasts is also going to result in the formation of TGF-beta, which in a feed forward loop will drive the tumor cells to make more of this hormone PTHrP.

03:27 So, you can see that this pretty quickly gets into a vicious cycle where you end up with higher and higher levels of calcium.

03:37 So just to kind of put this in a tabular form and how often does this happen in particular tumors, Overall, we already said that 10% of malignancies will have hypercalcemia.

03:50 In about 80% of breast cancers, lung cancers, non-Hodgkin lymphomas, there will be elevated PTHrP, which will cause the bone calcium releases we just discussed.

04:03 There are rare case reports of actually tumors, making honest to goodness, parathyroid hormone.

04:09 That will also act in the same general mechanisms to give you calcium release.

04:14 Some lymphomas, interestingly enough, will secrete an excess level of the activated form of vitamin D.

04:23 Very interesting, that will drive many the same effects that we have just seen.

04:27 This is how we modulate calcium levels normally, but if you have too high a level, due to a lymphoma that's making it, you'll get increased calcium absorption.

04:39 And finally, tumors that go to the bone and directly act on osteoblast to drive that RANK ligand expression, to cause the osteoclast resorb will give us osteolysis and 20% of breast, lung, myeloma.

04:55 We could also add in there. prostate cancers will do that.