December 6, 2025 • 15 mins
This episode maps the hidden biology of amyloidosis and explains how a small protein-folding error becomes a whole-body threat. Because this condition often hides behind strange, disconnected symptoms, early recognition is critical—and we break down the science in clear, practical language. You’ll learn how protein misfolding leads to amyloid deposits that damage the heart, kidneys, nerves, and GI tract, and why identifying the exact type of amyloidosis determines the right treatment.
We outline the differences between systemic vs. localized disease and why clinicians classify amyloidosis as primary or secondary to guide care decisions. You’ll learn the hallmarks of AL, ATTR, and AA amyloidosis, plus the surprising symptoms—like macroglossia, bruising around the eyes, neuropathy, swelling, or unexplained GI bleeding—that often confuse diagnosis. We explain how urine and blood tests, imaging, and biopsy confirm the cause, and highlight cardiac red flags detectable on echocardiogram and MRI.
The episode also covers modern treatments, from transthyretin stabilizers and gene silencers to chemotherapy and, in select cases, transplant. Finally, we explore prevention potential by controlling chronic inflammation and why prognosis depends heavily on type and stage at diagnosis.
High-volume keywords used: amyloidosis, protein misfolding, transthyretin, AL amyloidosis, cardiac amyloidosis, biopsy, chronic inflammation, early diagnosis
Listener Takeaways
- How protein misfolding creates organ-damaging amyloid deposits
- Key differences between AL, ATTR, AA, systemic, and localized disease
- Odd but important diagnostic clues that point to amyloidosis
- The tests and imaging needed for accurate, fast diagnosis
- Modern treatment options and why early detection is crucial
If you are experiencing unexplained persistent symptoms—especially issues that don’t seem connected, like extreme fatigue paired with breathing problems, swelling, or concerning bloody or black stools—contact a doctor and be persistent about getting a full evaluation.
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This podcast is created by Ai for educational and entertainment purposes only and does not constitute professional medical or health advice. Please talk to your healthcare team for medical advice.
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Transcript
Episode Transcript
Available transcripts are automatically generated. Complete accuracy is not guaranteed.
SPEAKER_00 (00:00):
Welcome to the deep dive.
If you're like most of us,you're probably drowning in
information, just searching forthat one source that can cut
through all the noise and giveyou the clear, precise knowledge
you need.
Well, that's our whole missionhere.
We take a huge stack of complexmaterial, we distill it, and we
deliver the essential insightsdirectly to you.
SPEAKER_01 (00:19):
Aaron Powell And today's topic is it's a big one.
SPEAKER_00 (00:22):
Aaron Powell It really is.
Today we are wrestling with atruly difficult, often tragic
medical mystery amyloidosis.
Right.
This is a disease that,according to all our sources, is
famously elusive.
It's often misdiagnosed andcauses, I mean, just a
staggering variety of symptoms.
SPEAKER_01 (00:39):
Trevor Burrus, Jr.: The ultimate medical mimic.
SPEAKER_00 (00:41):
Trevor Burrus, Jr.: Exactly.
It can strike virtually anyorgan in your body.
So imagine your body is thisperfect machine built with
billions of tiny parts, theseproteins, and they all have to
fold into very specific shapesto do their jobs.
Amyloidosis is what happens whenone of those proteins just folds
incorrectly.
Instead of slotting into place,it becomes sticky.
SPEAKER_01 (01:00):
Aaron Ross Powell Like a faulty piece of tape or
uh a ruined Lego brick.
SPEAKER_00 (01:05):
Aaron Powell Perfect analogy.
It can't be disposed of easily,so it just piles up, forming
these hard abnormal depositscalled amyloid.
Okay, let's unpack this.
What is the immediateconsequence of all this sticky
protein building up?
SPEAKER_01 (01:18):
Aaron Ross Powell The consequence is well, it's
systemic failure.
These amyloid deposits, they'reessentially space-occupying
lesions.
Right.
They just don't belong there andthey disrupt the normal function
of the organs.
And it's so crucial tounderstand, as you highlighted,
that this isn't a singledisease.
SPEAKER_00 (01:35):
Yeah.
SPEAKER_01 (01:36):
It's a whole collection of disorders.
And they're defined entirely bywhich protein is misfolding and
where it decides to accumulate.
SPEAKER_00 (01:42):
And that's really why the diagnostic process is
such a nightmare for you, thepatient.
I mean, when we were diving intothe medical literature for this,
the sheer range of symptoms onedisease could cause was it was
staggering.
Yeah.
What illness could possiblytouch the heart, the kidneys,
the nerves, and the digestivesystem all at once?
SPEAKER_01 (01:59):
Aaron Powell It is truly the ultimate systemic
threat.
I mean, consider the impact.
If the amyloid deposits settlein the heart, you might suffer
from severe heart failure, anenlarged heart, or maybe an
unstable rhythm that suddenlycauses problems.
SPEAKER_00 (02:13):
And if it's the kidneys.
SPEAKER_01 (02:15):
If it settles in the kidneys, you're looking at
kidney failure, or, and this isoften the very first sign,
excessive protein just showingup in the urine.
Trevor Burrus, Jr.
SPEAKER_00 (02:22):
And those are just the big hitters.
But what always makes thisdisease stick in my mind is the
truly surprising range ofsecondary symptoms.
Right.
I mean, think about it.
You could have severe weightloss, generalized weakness,
chronic diarrhea, which, youknow, a doctor might mistake for
irritable bowel syndrome.
SPEAKER_01 (02:39):
Very easily.
SPEAKER_00 (02:40):
All while you're also having joint pain and
swelling, making them think of,say, arthritis.
The sources even point out oneof the most distinctive and
frankly odd symptoms, anenlarged tongue.
The medical term ismacroglossia.
SPEAKER_01 (02:55):
Right, macroglossia.
SPEAKER_00 (02:56):
Imagine having such a swollen tongue that chewing or
swallowing becomes genuinelydifficult.
And then on top of all that, youmight get unusual bruising or
even intestinal bleeding thatcauses black terry stools.
SPEAKER_01 (03:08):
Often described as looking like coffee grounds.
SPEAKER_00 (03:11):
Exactly.
SPEAKER_01 (03:11):
And that combination of highly specific yet widely
disparate symptoms from aswollen tongue to heart failure,
that's why diagnosis is sodifficult.
Doctors test for the commondiseases first.
It's only natural.
SPEAKER_00 (03:24):
What's fascinating here is the ambiguity extends to
the root cause itself, right?
Aaron Powell It does.
SPEAKER_01 (03:30):
We know that in some cases the cause is just
completely unknown.
It just happens.
But in others, we can trace itback to either a specific
genetic mutation or criticallyto chronic prolonged
inflammation.
SPEAKER_00 (03:43):
Aaron Powell So the body is just overreacting for so
long that it starts making thesefaulty protein-building blocks.
SPEAKER_01 (03:48):
Aaron Powell That's a great way to put it, yes.
SPEAKER_00 (03:49):
Aaron Powell Now before we get to classification,
we need to clarify one hugepoint for you, the listener,
about brain amyloid.
Because when you hear proteindeposits and dementia, you
probably think of one thing.
SPEAKER_01 (04:00):
Aaron Powell Immediately Alzheimer's.
Absolutely.
And we have to be crystal clearhere.
Alzheimer's and other conditionslike criticillo choicup disease
do involve amyloid plaques.
Specifically a type called betaamyloid in Alzheimer's, but they
are distinct from the systemicamyloidosis we're mainly talking
about.
SPEAKER_00 (04:18):
Aaron Powell And why are they distinct?
SPEAKER_01 (04:20):
Well, because the type of protein is different and
the disease is generallylocalized just to the brain.
It's not threatening the entirebody at once, which is the
definition of systemicamyloidosis.
SPEAKER_00 (04:31):
Aaron Powell So the location of the misfold and the
type of the protein bothdetermine the clinical outcome.
And that leads us right intoclassification because doctors
have to identify the exactprotein to figure out the
treatment.
SPEAKER_01 (04:42):
Precisely.
SPEAKER_00 (04:43):
So the first classification system is
simpler (04:44):
primary versus secondary.
Primary amyloidosis means theproblem is just the protein
buildup itself.
There's no other cause.
SPEAKER_01 (04:51):
Right.
It's the core issue.
Right.
And secondary amyloidosis is theone where another disease is the
trigger.
SPEAKER_00 (04:57):
An existing disease.
SPEAKER_01 (04:58):
An existing disease, and it's almost always a chronic
inflammatory condition, likelong-standing untreated
tuberculosis or severe activerheumatoid arthritis.
SPEAKER_00 (05:09):
But the real diagnostic deep dive that needs
the modern system identifyingthe specific protein type.
SPEAKER_01 (05:15):
It does.
The modern system uses lettersbased on the protein source, and
our sources really focus on fourmajor categories.
SPEAKER_00 (05:23):
Okay, let's start with AL amyloid.
This is the most common primarytype.
The L stands for light chain.
SPEAKER_01 (05:29):
Part of an antibody produced by plasma cells, a type
of white blood cell.
SPEAKER_00 (05:32):
So these plasma cells are just producing way too
many of these abnormal antibodyparts that then fold
incorrectly.
SPEAKER_01 (05:39):
You've got it.
SPEAKER_00 (05:40):
Okay, here's where it gets really interesting.
Because these plasma cells arethe root of the problem, AL
amyloidosis is often associatedwith or a complication of
certain bone marrow cancers.
SPEAKER_01 (05:50):
Like multiple myeloma.
SPEAKER_00 (05:52):
Like multiple myeloma.
So we're talking about the samerunaway immune cells that are
causing the cancer are alsogenerating this harmful, sticky
protein.
SPEAKER_01 (05:59):
It's a powerful and dangerous connection.
Next is ATTR amyloid, where TTRstands for transtheridin.
SPEAKER_00 (06:06):
Transtheritin.
SPEAKER_01 (06:07):
Now, transtheritin is a protein that normally
carries really important thingslike thyroid hormones and
vitamin A through your body.
It's essential machinery.
Okay.
But in this condition, itmisfolds.
And the ATTR type can begenetic, a mutation passed down,
or it can be what we call wildtype, which is just caused by
the aging process itself.
SPEAKER_00 (06:27):
And this type is really destructive to the heart
and nerves.
SPEAKER_01 (06:30):
Highly destructive.
SPEAKER_00 (06:31):
Yeah.
SPEAKER_01 (06:32):
The protein that's supposed to be a good courier
turns into a toxic clog.
SPEAKER_00 (06:36):
Aaron Ross Powell So that's a brilliant question.
If its original job is socritical, like carrying
hormones, when it startsmisfolding, is the patient then
dealing with two problems, theclogging and the lack of hormone
transport?
SPEAKER_01 (06:48):
Aaron Powell That is a fantastic question.
And yes, while the primarylife-threatening concern is
definitely the depositsdisrupting organ function,
especially the heart.
Right.
The sheer fact that the proteinis structurally compromised
means its transport abilitiesare also affected.
It contributes to the overallsystemic decline.
But you know, the mechanicaldamage from the sticky plaque,
(07:08):
that's the immediate killer.
Trevor Burrus, Jr.
That makes perfect sense.
SPEAKER_00 (07:11):
Okay, what about the third major type?
AA amyloidosis.
SPEAKER_01 (07:16):
AA amyloidosis is that classic secondary type we
just talked about.
The AA comes from serum amyloidA protein.
SPEAKER_00 (07:23):
Okay.
SPEAKER_01 (07:23):
This is directly caused by chronic uncontrolled
inflammation.
It's from persistent infectionsor an autoimmune disease.
This is the body's prolongedstress response just going
completely haywire.
SPEAKER_00 (07:35):
And finally, we have that other category.
SPEAKER_01 (07:37):
Right, the catch-all captures everything else.
Familial types, those strictlyrelated to dialysis treatments
or amyloidosis that stayslocalized to just one spot, like
the skin or the GI tract.
SPEAKER_00 (07:48):
Aaron Powell But let's go back to that critical
distinction between primary andsecondary.
The source material reallyunderscores the massive
implication here.
Secondary types, that AAamyloidosis, they are
potentially preventable.
SPEAKER_01 (08:00):
And sometimes even reversible if the underlying
inflammation is successfullymanaged.
That's huge.
Think about that profoundly fora moment.
If you had severe rheumatoidarthritis decades ago, the
inflammation was a constantthreat, and the risk of
developing AA amyloidosis wasvery real and very debilitating.
SPEAKER_00 (08:17):
But today.
SPEAKER_01 (08:52):
It is.
These amyloid proteins can buildup silently for years before
symptoms get bad enough totrigger a specialist consult.
SPEAKER_00 (08:59):
So doctors start with standard tests.
SPEAKER_01 (09:01):
They do.
Standard but highly targeted.
They take a detailed family andmedical history, and during the
physical exam, they're lookingspecifically for signs of
systemic disease, abnormal heartsounds, skin discoloration, or
that unexplained swelling in thearms and legs.
SPEAKER_00 (09:14):
And the non-invasive tests can often point the way.
I know the urine test iscrucial.
SPEAKER_01 (09:18):
Absolutely crucial.
That excess protein showing upis a key early indicator that
something systemic is happening,especially with the kidneys.
And blood tests look forinflammatory markers, abnormal
counts, signs of organ damage.
SPEAKER_00 (09:32):
What about imaging?
SPEAKER_01 (09:33):
Imaging plays a massive role, especially
focusing on the heart.
An echocardiogram or a cardiacMRI can show heart enlargement
or a thickening of the walls.
SPEAKER_00 (09:42):
A classic sign.
SPEAKER_01 (09:43):
A classic sign of amyloid deposits, stiffening the
heart muscle.
They're looking forcircumstantial evidence,
essentially.
SPEAKER_00 (09:49):
But despite all those indicators, there's only
one way to know for sure.
The definitive test is thebiopsy.
SPEAKER_01 (09:56):
That is absolutely correct.
The only definitive test is tosurgically remove a small sample
of the affected tissue, stain itwith a special dye, usually
Congo red, and view it under amicroscope to confirm the
presence of that abnormalamyloid protein.
SPEAKER_00 (10:10):
And what about the location?
I mean, if the disease issystemic, affecting the whole
body, does the doctor have tocut open your heart or your
kidney to get that sample?
SPEAKER_01 (10:18):
Thankfully, no, not always.
For systemic amyloidosis, thediagnostic team is smart.
They often find that biopsiesfrom the abdominal fat pad or
even the rectum also containenough amyloid protein to
confirm the diagnosis.
SPEAKER_00 (10:32):
So much less invasive.
SPEAKER_01 (10:34):
Far less invasive.
However, if the amyloidosis islocalized, strictly limited to
the skin or the GI tract, thenthe biopsy must come from that
specific location.
SPEAKER_00 (10:44):
And that's where the risk comes in.
SPEAKER_01 (10:45):
That's where the inherent risk of diagnosis
becomes very apparent.
SPEAKER_00 (10:48):
That immediately makes me think back to the
brain.
If we suspect, say, cerebralamyloid angiopathy or
Alzheimer's, do doctors often doa brain biopsy?
SPEAKER_01 (10:58):
Generally, no, they don't.
And the sources explain why.
The risk of injury from taking abrain tissue sample is just
substantial.
Right.
And critically, the result oftendoesn't change the course of
treatment all that much,especially if the diagnosis can
be reasonably confirmed throughimaging and clinical assessment.
The risk just doesn't outweighthe reward.
SPEAKER_00 (11:16):
So once that definitive diagnosis is made,
the conversation moves totreatment.
And it's important to remindeveryone that amyloidosis is
usually a lifelong conditionthat, especially in primary
cases, can't be completelyreversed or cured.
SPEAKER_01 (11:30):
No, it's about management and slowing the
progression.
SPEAKER_00 (11:33):
Exactly.
SPEAKER_01 (11:33):
And again, the treatment strategy is entirely
dictated by the type.
For secondary amyloidosis, thegoal is always to aggressively
treat the underlyinginflammatory disease.
Stop the source, stop theprogression.
SPEAKER_00 (11:46):
Aaron Powell But for the primary types, we've moved
way beyond just managingsymptoms with general drugs like
corticosteroids or chemotherapy,which our sources note weren't
very effective in advancedcases.
SPEAKER_01 (11:57):
Aaron Powell Not at all.
The real shift is towardtargeted therapies.
SPEAKER_00 (12:00):
And we're seeing huge advances, especially for
that ATTR type, thetranstheratin disorder.
The FDA has approved drugs liketapimetis and petiserin.
SPEAKER_01 (12:09):
And this is where the science gets really
exciting.
Think back to our faulty proteinanalogy.
Tapimedes works by stabilizingthe transtheratin protein before
it can misfold.
It's like putting a splint on aperfectly good chair leg, so it
can't accidentally break andbecome that faulty Lego brick.
It dramatically slows down theaccumulation of new toxic
amyloid.
SPEAKER_00 (12:29):
That's incredible.
That's a genuine attempt tointerrupt the mechanism itself.
What about the other major typeslike AL amyloidosis, the one
linked to plasma cells?
SPEAKER_01 (12:38):
Aaron Powell Well, since the plasma cells are the
source, the treatment oftenaligns with cancer therapy.
High-intensity options likechemotherapy and even bone
marrow transplants can be highlyeffective.
SPEAKER_00 (12:48):
Because they eliminate the problem cells.
SPEAKER_01 (12:50):
Exactly.
The eliminate the problematicplasma cells.
It's a radical, high-risk,high-reward approach, but it
offers a path to halting theproduction of the toxic protein
altogether.
SPEAKER_00 (13:00):
Aaron Powell And we also have to mention the
anti-amyloid medicines that havemade headlines recently for
brain disorders.
The sources mention lacanimaband donanomab.
And these are approvedspecifically for slowing
cognitive impairment related tothe brain plaques we talked
about earlier.
SPEAKER_01 (13:14):
That's a paradigm shift.
These treatments aim to actuallyclear those existing plaques,
offering the first real hopethat we can intervene in the
progression of amyloid-relatedbrain diseases, even if they
aren't treating systemicamyloidosis.
SPEAKER_00 (13:28):
And then there's the last resort.
SPEAKER_01 (13:30):
The last resort.
For severely damaged organs,organ transplants, heart, liver,
or kidney, maybe the onlyremaining option for survival,
depending on the specific typeof the disease.
SPEAKER_00 (13:39):
So ultimately the prognosis is highly conditional.
SPEAKER_01 (13:42):
Highly conditional.
The outlook depends criticallyon two things: the exact type of
amyloidosis you have and thestage of organ impairment when
you're diagnosed.
If the heart or kidneys arealready severely damaged, the
path is much, much harder.
SPEAKER_00 (13:56):
Right.
SPEAKER_01 (13:56):
However, and this is important, we can end this
section with a needed note ofguarded optimism.
If we connect this to the biggerpicture, increased recognition
of amyloidoses.
SPEAKER_00 (14:06):
Which is huge.
SPEAKER_01 (14:08):
It's huge, thanks to awareness campaigns that
highlight these surprisingsymptoms, and improved targeted
therapies over the last decadehave undeniably led to improved
survival rates for manypatients.
SPEAKER_00 (14:18):
Absolutely.
So what does this all mean?
We've explored this hiddenmultisystemic threat defined by
an abnormal protein buildup.
This complexity means doctorshave to zero in on the exact
protein type, A-L-A-T-T-R, orAA, to guide therapy, because
the source is everything.
And despite this incrediblearray of sophisticated tests,
(14:38):
the definitive diagnosis alwayscomes down to that physical
tissue biopsy.
Oh, yes.
So if you are experiencingunexplained persistent symptoms,
especially things that justdon't seem to connect, like
extreme fatigue with breathingproblems or swelling, or that
concerning bloody or blackstool, it is absolutely
necessary to contact a doctorand be persistent about getting
a comprehensive look at yourhealth.
SPEAKER_01 (15:00):
And for a final provocative thought for you to
explore, we saw how theaggressive and successful
management of chronicinflammatory diseases, like
rheumatoid arthritis, hasessentially prevented the
development of secondary AAamyloidoses in many people.
Consider the profound, silentpublic health victory that
represents.
By managing one common disease,we inadvertently prevent a rare,
(15:22):
devastating complication yearsdown the line.
It really begs the question whatother chronic, subtle diseases
are we managing today that wemight not even realize are
preventing a major debilitatingcatastrophe 20 years from now?
SPEAKER_00 (15:35):
A fascinating insight into the power of
upstream thinking.
Thank you for joining us on thedeep dive.
We'll see you next time.
Welcome to the deep dive.
If you're like most of us,you're probably drowning in
information, just searching forthat one source that can cut
through all the noise and giveyou the clear, precise knowledge
you need.
Well, that's our whole missionhere.
We take a huge stack of complexmaterial, we distill it, and we
deliver the essential insightsdirectly to you.
SPEAKER_01 (00:19):
Aaron Powell And today's topic is it's a big one.
SPEAKER_00 (00:22):
Aaron Powell It really is.
Today we are wrestling with atruly difficult, often tragic
medical mystery amyloidosis.
Right.
This is a disease that,according to all our sources, is
famously elusive.
It's often misdiagnosed andcauses, I mean, just a
staggering variety of symptoms.
SPEAKER_01 (00:39):
Trevor Burrus, Jr.: The ultimate medical mimic.
SPEAKER_00 (00:41):
Trevor Burrus, Jr.: Exactly.
It can strike virtually anyorgan in your body.
So imagine your body is thisperfect machine built with
billions of tiny parts, theseproteins, and they all have to
fold into very specific shapesto do their jobs.
Amyloidosis is what happens whenone of those proteins just folds
incorrectly.
Instead of slotting into place,it becomes sticky.
SPEAKER_01 (01:00):
Aaron Ross Powell Like a faulty piece of tape or
uh a ruined Lego brick.
SPEAKER_00 (01:05):
Aaron Powell Perfect analogy.
It can't be disposed of easily,so it just piles up, forming
these hard abnormal depositscalled amyloid.
Okay, let's unpack this.
What is the immediateconsequence of all this sticky
protein building up?
SPEAKER_01 (01:18):
Aaron Ross Powell The consequence is well, it's
systemic failure.
These amyloid deposits, they'reessentially space-occupying
lesions.
Right.
They just don't belong there andthey disrupt the normal function
of the organs.
And it's so crucial tounderstand, as you highlighted,
that this isn't a singledisease.
SPEAKER_00 (01:35):
Yeah.
SPEAKER_01 (01:36):
It's a whole collection of disorders.
And they're defined entirely bywhich protein is misfolding and
where it decides to accumulate.
SPEAKER_00 (01:42):
And that's really why the diagnostic process is
such a nightmare for you, thepatient.
I mean, when we were diving intothe medical literature for this,
the sheer range of symptoms onedisease could cause was it was
staggering.
Yeah.
What illness could possiblytouch the heart, the kidneys,
the nerves, and the digestivesystem all at once?
SPEAKER_01 (01:59):
Aaron Powell It is truly the ultimate systemic
threat.
I mean, consider the impact.
If the amyloid deposits settlein the heart, you might suffer
from severe heart failure, anenlarged heart, or maybe an
unstable rhythm that suddenlycauses problems.
SPEAKER_00 (02:13):
And if it's the kidneys.
SPEAKER_01 (02:15):
If it settles in the kidneys, you're looking at
kidney failure, or, and this isoften the very first sign,
excessive protein just showingup in the urine.
Trevor Burrus, Jr.
SPEAKER_00 (02:22):
And those are just the big hitters.
But what always makes thisdisease stick in my mind is the
truly surprising range ofsecondary symptoms.
Right.
I mean, think about it.
You could have severe weightloss, generalized weakness,
chronic diarrhea, which, youknow, a doctor might mistake for
irritable bowel syndrome.
SPEAKER_01 (02:39):
Very easily.
SPEAKER_00 (02:40):
All while you're also having joint pain and
swelling, making them think of,say, arthritis.
The sources even point out oneof the most distinctive and
frankly odd symptoms, anenlarged tongue.
The medical term ismacroglossia.
SPEAKER_01 (02:55):
Right, macroglossia.
SPEAKER_00 (02:56):
Imagine having such a swollen tongue that chewing or
swallowing becomes genuinelydifficult.
And then on top of all that, youmight get unusual bruising or
even intestinal bleeding thatcauses black terry stools.
SPEAKER_01 (03:08):
Often described as looking like coffee grounds.
SPEAKER_00 (03:11):
Exactly.
SPEAKER_01 (03:11):
And that combination of highly specific yet widely
disparate symptoms from aswollen tongue to heart failure,
that's why diagnosis is sodifficult.
Doctors test for the commondiseases first.
It's only natural.
SPEAKER_00 (03:24):
What's fascinating here is the ambiguity extends to
the root cause itself, right?
Aaron Powell It does.
SPEAKER_01 (03:30):
We know that in some cases the cause is just
completely unknown.
It just happens.
But in others, we can trace itback to either a specific
genetic mutation or criticallyto chronic prolonged
inflammation.
SPEAKER_00 (03:43):
Aaron Powell So the body is just overreacting for so
long that it starts making thesefaulty protein-building blocks.
SPEAKER_01 (03:48):
Aaron Powell That's a great way to put it, yes.
SPEAKER_00 (03:49):
Aaron Powell Now before we get to classification,
we need to clarify one hugepoint for you, the listener,
about brain amyloid.
Because when you hear proteindeposits and dementia, you
probably think of one thing.
SPEAKER_01 (04:00):
Aaron Powell Immediately Alzheimer's.
Absolutely.
And we have to be crystal clearhere.
Alzheimer's and other conditionslike criticillo choicup disease
do involve amyloid plaques.
Specifically a type called betaamyloid in Alzheimer's, but they
are distinct from the systemicamyloidosis we're mainly talking
about.
SPEAKER_00 (04:18):
Aaron Powell And why are they distinct?
SPEAKER_01 (04:20):
Well, because the type of protein is different and
the disease is generallylocalized just to the brain.
It's not threatening the entirebody at once, which is the
definition of systemicamyloidosis.
SPEAKER_00 (04:31):
Aaron Powell So the location of the misfold and the
type of the protein bothdetermine the clinical outcome.
And that leads us right intoclassification because doctors
have to identify the exactprotein to figure out the
treatment.
SPEAKER_01 (04:42):
Precisely.
SPEAKER_00 (04:43):
So the first classification system is
simpler (04:44):
primary versus secondary.
Primary amyloidosis means theproblem is just the protein
buildup itself.
There's no other cause.
SPEAKER_01 (04:51):
Right.
It's the core issue.
Right.
And secondary amyloidosis is theone where another disease is the
trigger.
SPEAKER_00 (04:57):
An existing disease.
SPEAKER_01 (04:58):
An existing disease, and it's almost always a chronic
inflammatory condition, likelong-standing untreated
tuberculosis or severe activerheumatoid arthritis.
SPEAKER_00 (05:09):
But the real diagnostic deep dive that needs
the modern system identifyingthe specific protein type.
SPEAKER_01 (05:15):
It does.
The modern system uses lettersbased on the protein source, and
our sources really focus on fourmajor categories.
SPEAKER_00 (05:23):
Okay, let's start with AL amyloid.
This is the most common primarytype.
The L stands for light chain.
SPEAKER_01 (05:29):
Part of an antibody produced by plasma cells, a type
of white blood cell.
SPEAKER_00 (05:32):
So these plasma cells are just producing way too
many of these abnormal antibodyparts that then fold
incorrectly.
SPEAKER_01 (05:39):
You've got it.
SPEAKER_00 (05:40):
Okay, here's where it gets really interesting.
Because these plasma cells arethe root of the problem, AL
amyloidosis is often associatedwith or a complication of
certain bone marrow cancers.
SPEAKER_01 (05:50):
Like multiple myeloma.
SPEAKER_00 (05:52):
Like multiple myeloma.
So we're talking about the samerunaway immune cells that are
causing the cancer are alsogenerating this harmful, sticky
protein.
SPEAKER_01 (05:59):
It's a powerful and dangerous connection.
Next is ATTR amyloid, where TTRstands for transtheridin.
SPEAKER_00 (06:06):
Transtheritin.
SPEAKER_01 (06:07):
Now, transtheritin is a protein that normally
carries really important thingslike thyroid hormones and
vitamin A through your body.
It's essential machinery.
Okay.
But in this condition, itmisfolds.
And the ATTR type can begenetic, a mutation passed down,
or it can be what we call wildtype, which is just caused by
the aging process itself.
SPEAKER_00 (06:27):
And this type is really destructive to the heart
and nerves.
SPEAKER_01 (06:30):
Highly destructive.
SPEAKER_00 (06:31):
Yeah.
SPEAKER_01 (06:32):
The protein that's supposed to be a good courier
turns into a toxic clog.
SPEAKER_00 (06:36):
Aaron Ross Powell So that's a brilliant question.
If its original job is socritical, like carrying
hormones, when it startsmisfolding, is the patient then
dealing with two problems, theclogging and the lack of hormone
transport?
SPEAKER_01 (06:48):
Aaron Powell That is a fantastic question.
And yes, while the primarylife-threatening concern is
definitely the depositsdisrupting organ function,
especially the heart.
Right.
The sheer fact that the proteinis structurally compromised
means its transport abilitiesare also affected.
It contributes to the overallsystemic decline.
But you know, the mechanicaldamage from the sticky plaque,
(07:08):
that's the immediate killer.
Trevor Burrus, Jr.
That makes perfect sense.
SPEAKER_00 (07:11):
Okay, what about the third major type?
AA amyloidosis.
SPEAKER_01 (07:16):
AA amyloidosis is that classic secondary type we
just talked about.
The AA comes from serum amyloidA protein.
SPEAKER_00 (07:23):
Okay.
SPEAKER_01 (07:23):
This is directly caused by chronic uncontrolled
inflammation.
It's from persistent infectionsor an autoimmune disease.
This is the body's prolongedstress response just going
completely haywire.
SPEAKER_00 (07:35):
And finally, we have that other category.
SPEAKER_01 (07:37):
Right, the catch-all captures everything else.
Familial types, those strictlyrelated to dialysis treatments
or amyloidosis that stayslocalized to just one spot, like
the skin or the GI tract.
SPEAKER_00 (07:48):
Aaron Powell But let's go back to that critical
distinction between primary andsecondary.
The source material reallyunderscores the massive
implication here.
Secondary types, that AAamyloidosis, they are
potentially preventable.
SPEAKER_01 (08:00):
And sometimes even reversible if the underlying
inflammation is successfullymanaged.
That's huge.
Think about that profoundly fora moment.
If you had severe rheumatoidarthritis decades ago, the
inflammation was a constantthreat, and the risk of
developing AA amyloidosis wasvery real and very debilitating.
SPEAKER_00 (08:17):
But today.
SPEAKER_01 (08:52):
It is.
These amyloid proteins can buildup silently for years before
symptoms get bad enough totrigger a specialist consult.
SPEAKER_00 (08:59):
So doctors start with standard tests.
SPEAKER_01 (09:01):
They do.
Standard but highly targeted.
They take a detailed family andmedical history, and during the
physical exam, they're lookingspecifically for signs of
systemic disease, abnormal heartsounds, skin discoloration, or
that unexplained swelling in thearms and legs.
SPEAKER_00 (09:14):
And the non-invasive tests can often point the way.
I know the urine test iscrucial.
SPEAKER_01 (09:18):
Absolutely crucial.
That excess protein showing upis a key early indicator that
something systemic is happening,especially with the kidneys.
And blood tests look forinflammatory markers, abnormal
counts, signs of organ damage.
SPEAKER_00 (09:32):
What about imaging?
SPEAKER_01 (09:33):
Imaging plays a massive role, especially
focusing on the heart.
An echocardiogram or a cardiacMRI can show heart enlargement
or a thickening of the walls.
SPEAKER_00 (09:42):
A classic sign.
SPEAKER_01 (09:43):
A classic sign of amyloid deposits, stiffening the
heart muscle.
They're looking forcircumstantial evidence,
essentially.
SPEAKER_00 (09:49):
But despite all those indicators, there's only
one way to know for sure.
The definitive test is thebiopsy.
SPEAKER_01 (09:56):
That is absolutely correct.
The only definitive test is tosurgically remove a small sample
of the affected tissue, stain itwith a special dye, usually
Congo red, and view it under amicroscope to confirm the
presence of that abnormalamyloid protein.
SPEAKER_00 (10:10):
And what about the location?
I mean, if the disease issystemic, affecting the whole
body, does the doctor have tocut open your heart or your
kidney to get that sample?
SPEAKER_01 (10:18):
Thankfully, no, not always.
For systemic amyloidosis, thediagnostic team is smart.
They often find that biopsiesfrom the abdominal fat pad or
even the rectum also containenough amyloid protein to
confirm the diagnosis.
SPEAKER_00 (10:32):
So much less invasive.
SPEAKER_01 (10:34):
Far less invasive.
However, if the amyloidosis islocalized, strictly limited to
the skin or the GI tract, thenthe biopsy must come from that
specific location.
SPEAKER_00 (10:44):
And that's where the risk comes in.
SPEAKER_01 (10:45):
That's where the inherent risk of diagnosis
becomes very apparent.
SPEAKER_00 (10:48):
That immediately makes me think back to the
brain.
If we suspect, say, cerebralamyloid angiopathy or
Alzheimer's, do doctors often doa brain biopsy?
SPEAKER_01 (10:58):
Generally, no, they don't.
And the sources explain why.
The risk of injury from taking abrain tissue sample is just
substantial.
Right.
And critically, the result oftendoesn't change the course of
treatment all that much,especially if the diagnosis can
be reasonably confirmed throughimaging and clinical assessment.
The risk just doesn't outweighthe reward.
SPEAKER_00 (11:16):
So once that definitive diagnosis is made,
the conversation moves totreatment.
And it's important to remindeveryone that amyloidosis is
usually a lifelong conditionthat, especially in primary
cases, can't be completelyreversed or cured.
SPEAKER_01 (11:30):
No, it's about management and slowing the
progression.
SPEAKER_00 (11:33):
Exactly.
SPEAKER_01 (11:33):
And again, the treatment strategy is entirely
dictated by the type.
For secondary amyloidosis, thegoal is always to aggressively
treat the underlyinginflammatory disease.
Stop the source, stop theprogression.
SPEAKER_00 (11:46):
Aaron Powell But for the primary types, we've moved
way beyond just managingsymptoms with general drugs like
corticosteroids or chemotherapy,which our sources note weren't
very effective in advancedcases.
SPEAKER_01 (11:57):
Aaron Powell Not at all.
The real shift is towardtargeted therapies.
SPEAKER_00 (12:00):
And we're seeing huge advances, especially for
that ATTR type, thetranstheratin disorder.
The FDA has approved drugs liketapimetis and petiserin.
SPEAKER_01 (12:09):
And this is where the science gets really
exciting.
Think back to our faulty proteinanalogy.
Tapimedes works by stabilizingthe transtheratin protein before
it can misfold.
It's like putting a splint on aperfectly good chair leg, so it
can't accidentally break andbecome that faulty Lego brick.
It dramatically slows down theaccumulation of new toxic
amyloid.
SPEAKER_00 (12:29):
That's incredible.
That's a genuine attempt tointerrupt the mechanism itself.
What about the other major typeslike AL amyloidosis, the one
linked to plasma cells?
SPEAKER_01 (12:38):
Aaron Powell Well, since the plasma cells are the
source, the treatment oftenaligns with cancer therapy.
High-intensity options likechemotherapy and even bone
marrow transplants can be highlyeffective.
SPEAKER_00 (12:48):
Because they eliminate the problem cells.
SPEAKER_01 (12:50):
Exactly.
The eliminate the problematicplasma cells.
It's a radical, high-risk,high-reward approach, but it
offers a path to halting theproduction of the toxic protein
altogether.
SPEAKER_00 (13:00):
Aaron Powell And we also have to mention the
anti-amyloid medicines that havemade headlines recently for
brain disorders.
The sources mention lacanimaband donanomab.
And these are approvedspecifically for slowing
cognitive impairment related tothe brain plaques we talked
about earlier.
SPEAKER_01 (13:14):
That's a paradigm shift.
These treatments aim to actuallyclear those existing plaques,
offering the first real hopethat we can intervene in the
progression of amyloid-relatedbrain diseases, even if they
aren't treating systemicamyloidosis.
SPEAKER_00 (13:28):
And then there's the last resort.
SPEAKER_01 (13:30):
The last resort.
For severely damaged organs,organ transplants, heart, liver,
or kidney, maybe the onlyremaining option for survival,
depending on the specific typeof the disease.
SPEAKER_00 (13:39):
So ultimately the prognosis is highly conditional.
SPEAKER_01 (13:42):
Highly conditional.
The outlook depends criticallyon two things: the exact type of
amyloidosis you have and thestage of organ impairment when
you're diagnosed.
If the heart or kidneys arealready severely damaged, the
path is much, much harder.
SPEAKER_00 (13:56):
Right.
SPEAKER_01 (13:56):
However, and this is important, we can end this
section with a needed note ofguarded optimism.
If we connect this to the biggerpicture, increased recognition
of amyloidoses.
SPEAKER_00 (14:06):
Which is huge.
SPEAKER_01 (14:08):
It's huge, thanks to awareness campaigns that
highlight these surprisingsymptoms, and improved targeted
therapies over the last decadehave undeniably led to improved
survival rates for manypatients.
SPEAKER_00 (14:18):
Absolutely.
So what does this all mean?
We've explored this hiddenmultisystemic threat defined by
an abnormal protein buildup.
This complexity means doctorshave to zero in on the exact
protein type, A-L-A-T-T-R, orAA, to guide therapy, because
the source is everything.
And despite this incrediblearray of sophisticated tests,
(14:38):
the definitive diagnosis alwayscomes down to that physical
tissue biopsy.
Oh, yes.
So if you are experiencingunexplained persistent symptoms,
especially things that justdon't seem to connect, like
extreme fatigue with breathingproblems or swelling, or that
concerning bloody or blackstool, it is absolutely
necessary to contact a doctorand be persistent about getting
a comprehensive look at yourhealth.
SPEAKER_01 (15:00):
And for a final provocative thought for you to
explore, we saw how theaggressive and successful
management of chronicinflammatory diseases, like
rheumatoid arthritis, hasessentially prevented the
development of secondary AAamyloidoses in many people.
Consider the profound, silentpublic health victory that
represents.
By managing one common disease,we inadvertently prevent a rare,
(15:22):
devastating complication yearsdown the line.
It really begs the question whatother chronic, subtle diseases
are we managing today that wemight not even realize are
preventing a major debilitatingcatastrophe 20 years from now?
SPEAKER_00 (15:35):
A fascinating insight into the power of
upstream thinking.
Thank you for joining us on thedeep dive.
We'll see you next time.
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