Amyloidosis is a group of diseases in which abnormal proteins, known as amyloid fibrils, build up in tissue. Symptoms depend on the type and are often variable. They may include diarrhea, weight loss, feeling tired, enlargement of the tongue, bleeding, numbness, feeling faint with standing, swelling of the legs, or enlargement of the spleen.
There are about 30 different types of
amyloidosis, each due to a specific protein misfolding. Some are genetic while
others are acquired. They are grouped into localized and systemic forms. The
four most common types of systemic disease are light chain (AL), inflammation
(AA), dialysis (Aβ2M), and hereditary and old age (ATTR).
Diagnosis may be suspected when protein
is found in the urine, organ enlargement is present, or problems are found with
multiple peripheral nerves and it is unclear why. Diagnosis is confirmed by tissue
biopsy. Due to the variable presentation, a diagnosis can often take some time
to reach.
Treatment is geared towards decreasing
the amount of the involved protein. This may sometimes be achieved by
determining and treating the underlying cause. AL amyloidosis occurs in about
3–13 per million people per year and AA amyloidosis in about 2 per million
people per year. The usual age of onset of these two types is 55 to 60 years
old. Without treatment, life expectancy is between six months and four years. In
the developed world about 1 per 1,000 people die from amyloidosis. Amyloidosis
has been described since at least 1639.
Pathogenesis
The cells in the body have two different
ways of making proteins. Some proteins are made of one single piece or sequence
of amino acids; in other cases, protein fragments are produced, and the
fragments come and join together to form the whole protein. But such a protein
can sometimes fall apart into the original protein fragments. This process of
"flip flopping" happens frequently for certain protein types, especially
the ones that cause amyloidosis.
The fragments or actual proteins are at
risk of misfolding as they are synthesized, to make a poorly functioning
protein. This causes proteolysis, which is the directed breakdown of proteins
by cellular enzymes called proteases or by intramolecular digestion; proteases
come and digest the misfolded fragments and proteins. The problem occurs when
the proteins do not dissolve in proteolysis because the misfolded proteins
sometimes become robust enough such that they are not dissolved by normal
proteolysis. When the fragments do not dissolve, they get spit out of
proteolysis and aggregate to form oligomers. The reason they aggregate is that
the parts of the protein that do not dissolve in proteolysis are hydrophobic β-pleated
sheets. They are usually sequestered in the middle of the protein, while parts
of the protein that are more soluble are found near the outside. When they are
exposed to water, these hydrophobic pieces tend to aggregate with other
hydrophobic pieces. This ball of fragments gets stabilized by GAGs
(glycosaminoglycans) and SAP (serum amyloid P), a component found in amyloid
aggregations that is thought to stabilize them and prevent proteolytic
cleavage. The stabilized balls of protein fragments are called oligomers. The
oligomers can aggregate together and further stabilize to make amyloid fibrils.
Both the oligomers and amyloid fibrils
are toxic to cells and can interfere with proper organ function.
Diagnosis
Diagnosis of amyloidosis generally
requires tissue biopsy. The biopsy is assessed for evidence of characteristic
amyloid deposits. The tissue is treated with various stains. The most useful
stain in the diagnosis of amyloid is Congo red, which, combined with polarized
light, makes the amyloid proteins appear apple-green on microscopy. Also, thioflavin
T stain may be used. A number of imaging techniques such as a DPD scan or SAP
scan are also in use.
Tissue can come from any involved organ,
but in systemic disease the first-line site of the biopsy is subcutaneous
abdominal fat, known as a "fat pad biopsy", due to its ease of
acquisition versus biopsy of the rectum, salivary gland or internal organs. An
abdominal fat biopsy is not completely sensitive, and sometimes, biopsy of an
involved organ (such as the kidney) is required to achieve a diagnosis. For
example, in AL amyloidosis only 85% of people will have a positive fatpad
biopsy using Congo red stain. By comparison, rectal biopsy has sensitivity of
74–94%.
In the amyloid deposition of the joints,
there will be a decreased signal in both T1 and T2 weighted MRI images. In
amyloidoma, there will be low T1 signal with gadolinium injection and low T2
signal.
The type of the amyloid protein can be
determined in various ways: the detection of abnormal proteins in the
bloodstream (on protein electrophoresis or light chain determination); binding
of particular antibodies to the amyloid found in the tissue
(immunohistochemistry); or extraction of the protein and identification of its
individual amino acids. Immunohistochemistry can identify AA amyloidosis the
majority of the time, but can miss many cases of AL amyloidosis. Laser
microdissection with mass spectrometry is the most reliable method of
identifying the different forms of amyloidosis.
AL is the most common form of
amyloidosis, and a diagnosis often begins with a search for plasma cell
dyscrasia, memory B cells producing aberrant immunoglobulins or portions of
immunoglobulins. Immunofixation electrophoresis of urine or serum is positive
in 90% of people with AL amyloidosis. Immunofixation electrophoresis is more
sensitive than regular electrophoresis but may not be available in all centers.
Alternatively immunohistochemical staining of a bone marrow biopsy looking for
dominant plasma cells can be sought in people with a high clinical suspicion
for AL amyloidosis but negative electrophoresis.
ATTR, or familial
transthyretin-associated amyloidosis, is suspected in people with family
history of idiopathic neuropathies or heart failure who lack evidence of plasma
cell dyscrasias. ATTR can be identified using isoelectric focusing, which
separates mutated forms of transthyretin. Findings can be corroborated by
genetic testing to look for specific known mutations in transthyretin that
predispose to amyloidosis.
AA is suspected on clinical grounds in
individuals with longstanding infections or inflammatory diseases. AA can be
identified by immunohistochemistry staining.
Treatment
Treatment depends on the type of
amyloidosis that is present. Treatment with high dose melphalan, a chemotherapy
agent, followed by stem cell transplantation has shown promise in early studies
and is recommended for stage I and II AL amyloidosis. However, only 20–25% of
people are eligible for stem cell transplant. Chemotherapy and steroids, with
melphalan plus dexamethasone, is mainstay treatment in AL people not eligible
for transplant.
In AA, symptoms may improve if the
underlying condition is treated; eprodisate has been shown to slow renal
impairment by inhibiting polymerization of amyloid fibrils.
In ATTR, liver transplant is a curative
therapy because mutated transthyretin which forms amyloids is produced in the
liver.
In 2018, patisiran was not recommended
by NICE in the UK for hereditary transthyretin-related amyloidosis. As of July
2019 further review however is occurring. It was approved for this use in the
United States however.
Prognosis
Prognosis varies with the type of
amyloidosis. Prognosis for untreated AL amyloidosis is poor, with median
survival of one to two years. More specifically, AL amyloidosis can be
classified as stage I, II or III based on cardiac biomarkers like troponin and
BNP. Survival diminishes with increasing stage, with estimated survival of 26,
11 and 3.5 months at stages I, II and III, respectively.
Outcomes in a person with AA amyloidosis
depend on the underlying disease and correlate with the concentration of serum
amyloid A protein.
People with ATTR have a better prognosis
and may survive for over a decade.
Senile systemic amyloidosis was
determined to be the primary cause of death for 70% of people over 110 who
have been autopsied.
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