Amyloidosis – causes, symptoms, diagnosis, treatment, pathology

In amyloidosis, “amyloid” refers to starch-like,
and it goes back to an observation made by the German scientist Rudolf Virchow, who saw
mysterious deposits in the tissue that stained blue with iodine, just like plant starch. As it turns out, amyloids are actually just
proteins that take on an abnormal shape, which makes them stick together and settle in tissues. And amyloidosis is the name for the disease
that develops as a result of the tissue damage from these protein deposits. Normally, our cells produce thousands of proteins
each and every moment, and these proteins need to fold into a particular shape in order
to do their jobs properly. If a protein folds incorrectly, it’s normally
spotted right away and destroyed by proteases, which are enzymes that chop up larger proteins
into tiny bits. In amyloidosis, there are a few different
ways that protein folding can go wrong. One way is when normal proteins are produced
in enormous amounts, and just a small fraction of them fold incorrectly. A second option is that abnormal proteins
with incorrect amino acid sequences are produced in normal amounts, and they fold incorrectly. Either way, the misfolded proteins, called
amyloids start to build up. Sometimes there’s simply too many of them
for the protease to handle, and other times, the way that they’re folded makes them tough
to break down – a bit like a pistachio that doesn’t have an opening for your fingers
to work with. Nightmare. When the amyloid proteins get excreted out
of the cell, they tend to clump together forming a rigid, insoluble structure called a β-sheet
– like a folded sheet of paper. These β- sheets then deposit in the extracellular
space of tissues and cause damage. So amyloidosis is a process where there are
extra protein deposits, and there are many different proteins and diseases that follow
that same underlying process. In general, amyloidosis can be systemic, meaning
that those protein deposits occur in multiple organ systems, or it can be localized, meaning
that they occur in one organ. Until recently, systemic amyloidosis was further
broken down into primary amyloidosis, which is where amyloidosis was thought to be the
main problem, and secondary amyloidosis, which is where there was another known disease process
that resulted in the protein deposits. However, this is not totally accurate, since
an underlying disease process has been identified even in the primary form. OK, so, AL amyloidosis, previously known as
primary amyloidosis, is where “A” refers to amyloidosis and “L” refers to the immunoglobulin
light chain as the protein that gets misfolded and deposited. In plasma cell disorders, like multiple myeloma,
plasma cells in the bone marrow produce more light chains than heavy chains, and those
excess light chains leak out into the blood. Since there are so many light chains, some
misfold into AL proteins, and build up in various tissues. In AA amyloidosis, previously known as secondary
amyloidosis the misfolded protein comes from serum amyloid A. Under normal conditions,
serum amyloid A is a properly folded protein that’s an acute phase reactant meaning that
it’s secreted into the bloodstream by the liver whenever there’s inflammation. But when inflammation goes on for too long,
like in rheumatoid arthritis, inflammatory bowel disease, various cancers, or hereditary
immune disorders like Familial Mediterranean fever, there’s lots of serum amyloid A in
the blood. And a small proportion of the serum amyloid
A spontaneously folds incorrectly into AA amyloids, which end up accumulating within
tissues creating amyloidosis. In systemic amyloidosis, amyloids deposit
in various organs. In the kidneys, amyloid deposits can damage
the podocytes, which are the cells that line the glomerulus. When the podocytes are damaged, proteins like
albumin spill into the urine, which results in proteinuria – protein in the urine, typically
greater than 3.5 grams per day and hypoalbuminemia – which is low albumin in the blood. Over time, with less protein in the blood
the oncotic pressure falls, and that drives water out of the blood vessels and into the
tissues, called edema. Albumin and other proteins that normally inhibit
the synthesis of lipids, or fat, so losing them leads to hyperlipidemia – which is increased
levels of lipid in the blood. Those are the hallmarks of nephrotic syndrome—proteinuria,
hypoalbuminemia, edema, and hyperlipidemia. Now, in the heart, amyloid deposits can make
the heart walls stiff and non-compliant and that can lead to restrictive cardiomyopathy,
which is when the ventricle is unable to stretch out and fill up with blood. Over time that can lead to congestive heart
failure. Amyloid deposits can also interfere with the
electrical conduction system of the heart, causing arrhythmias, or an irregular heartbeat. In the intestines, amyloid deposits can damage
the tips of intestinal villi which are the tiny fingerlike projections that increase
the surface area available for absorbing nutrients. When the villi are damaged, nutrients don’t
get absorbed and simply end up in the stool. Amyloid deposits can also build up in the
liver, spleen, or tongue, making them enlarge. Finally, amyloid deposits can injure peripheral
nerve fibers, like the ones carrying sensory or motor signals, or autonomic nerves that
control things like digestion and blood pressure. In localized amyloidosis, amyloid deposits
in a single organ. And a well-known example is Alzheimer’s
disease. Alzheimer’s is a neurodegenerative disease
caused when proteins called Aβ peptides collect in one organ – the brain. These Αβ peptides clump together and form
plaques that sit outside of neurons and interfere with neuron- to- neuron signaling. Amyloid plaques also deposit in the walls
of blood vessels in the brain, called amyloid angiopathy, which weakens the walls of the
blood vessels and increases the risk of hemorrhage or rupture. These plaques can trigger an inflammatory
response and that can cause damage to the neurons – over time leading to problems with
brain functions like memory. Another example of localized amyloidosis is
familial amyloid cardiomyopathy, also known as ATTR amyloidosis. This is a genetic disorder where mutant transthyretin
protein, or TTR, is misfolded and deposits in heart tissue, causing restrictive cardiomyopathy. In contrast, there’s also senile cardiac
amyloidosis, which is when normal TTR protein gradually begins to deposit in the heart. This only becomes a problem, though, when
it has gone on for a long time – so it mostly affects the elderly. Amyloids can also deposit is the pancreas. For example, in diabetes mellitus type II,
the beta- cells of the pancreas, found in the islets of langerhans, pump out more insulin
than normal. But along with increased insulin production
beta- cells also secrete an increased amount of a protein called islet amyloid peptide,
or amylin. Over time, amylin aggregates between beta
cells in the islets of the pancreas, causing inflammation which leads to damage and beta
cell death. The symptoms of amyloidosis vary widely. With kidney damage, there swelling in the
face, ankles, and legs, heart damage can lead to palpitations and shortness of breath, and
intestinal damage can cause malabsorption and weight loss. Some individuals develop a large tongue which
can interfere with speech and swallowing, and cause noisy breathing at night. Nerve damage can lead to numbness or pain
in the fingers and toes, as well as alternating bouts of diarrhea and constipation, or orthostatic
hypotension, meaning that blood pressure falls, causing the person to feel light- headed,
whenever they are standing up. The central nervous system is often spared,
except in Alzheimer’s disease, where the main symptom is memory loss and difficulty
learning new skills. The diagnosis of amyloidosis typically requires
a biopsy of the involved organ or by doing a “fat pad biopsy” which is when fat is
taken from the abdomen. The sample is then dyed with a special Congo
red staining, which makes amyloid take on a characteristic pink color. When it’s seen under polarized light, the
amyloid proteins appear apple-green in color. Unfortunately, there’s no way to effectively
remove the amyloid deposits, so if there’s extensive damage to an organ, than organ transplantation
can be tried. OK, so, let’s have a quick recap, then. Amyloidosis is caused by misfolded amyloid
fibrils deposits which can be systemic, in multiple organ systems, like the kidney, the
heart, and intestines, or localized to the brain in Alzheimer’s disease or the pancreas
in diabetes mellitus type II. In tissue biopsy, Congo red stain makes the
amyloid proteins go pink and under polarized light they appear apple-green.