Hypercalcemia, the next paraneoplastic
process we're going to discuss.
Hypercalcemia is the most common metabolic
abnormality that occurs in malignancy.
In about 10% of malignancies, pretty high
percentage, will have some degree of hypercalcemia.
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.
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.
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.
All this is going to be exacerbated by renal failure.
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.
The symptoms are somewhat nonspecific.
In fact, many of you have probably memorized
the stones, bones, groans and moans.
Those are kind of the
manifestations of hypercalcemia.
So stones, you can get renal
calculi due to calcium phosphate.
Bones, because we're resorbing from the bone.
Groans, you can have GI symptoms and
moans are the neuropsychiatric effects.
So if you remember those, that's kind
of how hypercalcemia manifestations.
And if the calcium level gets too
high can result in coma and death.
So how is this happening?
Kind of in a schematic here, we have
tumor cells that are releasing that
parathyroid hormone-related protein.
That hormone can act to grease to
stimulate calcium reabsorption.
So normally, the kidney would
be putting out excess calcium.
This stimulates the renal tubular epithelial cells
to pull back more calcium, so the level goes up.
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.
So that will elevate the
calcium levels as you see there.
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.
So, you can see that this pretty
quickly gets into a vicious cycle
where you end up with higher
and higher levels of calcium.
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.
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.
There are rare case reports of actually tumors,
making honest to goodness, parathyroid hormone.
That will also act in the same general
mechanisms to give you calcium release.
Some lymphomas, interestingly enough, will
secrete an excess level of the activated
form of vitamin D.
Very interesting, that will drive many
the same effects that we have just seen.
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.
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.
We could also add in there.
prostate cancers will do that.