RUNNING HEAD: AMYLOIDOSIS

Amyloidosis
Jill Matsuoka
RTH 291
Argosy University
Fall 2014

Introduction

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Amyloidosis is a rare disorder comprised of a diverse group of multisystem diseases that

occurs when folded proteins called amyloids are deposited and build up in tissue (Mayo Clinic,
2014, para. 1). Protein is typically water soluble, but when they fold they become insoluble,
fibrous and form fibrils that accumulate in tissue thus interfering with the normal function of
organs and muscles (Pinney & Hawkins, 2012, p. 229). The clinical manifestation of
amyloidosis is dependent upon the type of protein affected and into what type of tissue or organ
the amyloids are deposited (Pinney & Hawkins, 2012, p. 229). The results can be localized or
systemic and, in the most serious cases, can be fatal. Amyloidosis is a very poorly understood
disease with very limited research and treatment options, although that is beginning to change
with hopes that awareness will lead to advanced research and alternate treatment modalities.

Case Study

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Patient R is a 61 year old female who first sought medical care in January of 2008 for a
nodule in the posterior portion of her left calf. The nodule was located in the deep subcutaneous
tissue of the calf, approximately 2 cm in diameter and was tender to palpation. After undergoing
an incisional biopsy she was thought to have nodular dermal amyloidosis. The patient then
underwent urinalysis, an echocardiogram, and fat aspiration that all tested negative for systemic
disease.
In 2009 the patient returned for a follow-up and again tested negative for systemic
disease. The pain in her left calf had gotten worse although there was also no evidence of further
localized disease. It was recommended she undergo radiation therapy for the treatment of her
nodule. The suggested dose was 10 to 20 Gy if an MRI showed definitive evidence of amyloids.
Patient R decided to forgo treatment at that time.
In March 2013 the patient again sought medical care as her pain had significantly
increased. There were also additional nodules in her left posterior calf as well as a new nodule in
her right calf measuring approximately 10 cm in diameter. The new nodules were biopsied and
were positive for localized amyloidosis or localized AL (amyloidosis light chain), which is
extremely rare (Holmes, 2014, p. 2). The patient again went through a full systemic workup and
no systemic disease was found. In September of 2013 it was again suggested that she undergo
radiation therapy treatments for her nodules, although this time at 20 to 30 Gy.
Patient R came for a consultation with the radiation oncologist in March 2014. Although
she had no signs of edema or cyanosis the patient averaged her pain to be 8 out of 10 on the pain
scale. The pain was worse upon standing and walking, but was relieved somewhat with rest.
The lesions were not visible but extremely tender when palpated and were beginning to affect her

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ambulation. She also complained of pain when swallowing so was sent for another round of
tests to rule out systemic involvement. Again, urinalysis and echocardiogram ruled out systemic
involvement as did her PET/CT which showed uptake solely in the nodules confined to her legs.
On May 15, 2014 Patient R began bilateral leg radiation therapy in our department. She
was positioned supine on the table, feet first and we utilized a rice box and rice bolus bilaterally.
Her primary fields were AP/PA and laterals on both legs, with a clinical boost. She was treated
with 10 MV photons for 10 fractions totaling 20 Gy, then boosted with 6 MeV electrons for 5
days for a total of 10 Gy. In all, the patient received 30 Gy in the course of 19 days. The patient
experienced mild tanning and grade 1-2 erythema but tolerated the treatment very well.
Following the end of treatment, she was still experiencing quite a bit of pain and approximated it
had been reduced by less than 50 percent.
Patient R returned for a follow up examination in October 2014. Unfortunately her
lesions were still present; nevertheless, there was no increase in size with the exception of one
nodule on her right leg. She believed the pain had become slightly worse and was greatly
affecting her gait. The patient will occasionally take a hydrocodone but is very hesitant to take
anything stronger than over the counter medicines. Chemotherapy may be an option for her, but
in the past the patient was not open to that treatment modality. Patient R was seeing a medical
oncologist to discuss alternate treatment options. There was no more that we could do for her
with radiation at that time so the patient is to be seen as needed.

Discussion

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Amyloidosis is a rare disease that inflicts approximately 1 or 2 individuals out of every 1

million (Cancer.net, 2013). Amyloidosis is classified chemically, or by the fibril proteins, and
currently there are at least 25 known fibrils that produce amyloids in the human body (Pinney &
Hawkins, 2012, p. 229). Types of amyloids are very diverse in that they can be localized or
systemic, genetic or acquired, and slow or rapidly growing (Pinney & Hawkins, 2012, p. 229).
Additionally, the anatomical dissemination can vary greatly between the different types and even
occasionally within the same type. Due to these anomalies, it is crucial that pathological
diagnosis and comprehensive clinical evaluation are exact for management of the disease
(Pinney & Hawkins, 2012, p. 229).
Although not required, I feel it necessary to discuss a few different types of amyloidosis.
This is a disease not commonly seen in radiation therapy and I believe a better understanding is
essential for the purposes of this paper. The focus will be on the three most common types:
Primary or AL, Secondary or AA, and Familial or ATTR (BU Amyloidosis Center, n.d.). I will
also briefly discuss localized amyloidosis.
Primary amyloidosis or AL is a rare hematologic disorder that affects an estimated
1200 to 3200 Americans each year (Amyloidosis Foundation, n.d.). AL is an acquired, systemic
disease characterized by irregular monoclonal immunoglobin light chain proteins that are
produced in the bone marrow and most often found in the urine or blood (BU Amyloidosis
Center, n.d.). Al is very similar to multiple myeloma which is also a plasma disorder; and,
roughly 15 percent of patients will present with concurrent multiple myeloma (Amyloidosis
Foundation, n.d.; Pinney & Hawkins, 2012, p. 232). With the exception of the central nervous
system, primary amyloidosis can affect any organ in the body with kidneys, heart, liver, and
autonomic or peripheral nerves being the most common (Amyloidosis Foundation, n.d.).

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Common side effects are dependent upon location of the fibril deposits but can include shortness
of breath, edema, neuropathy, protein in the urine or kidney failure, enlarged tongue, heart
failure, and hepatomegaly (BU Amyloidosis Center, n.d.).
Secondary amyloidosis or AA is a complication of chronic infection or inflammatory
conditions (BU Amyloidosis Center, n.d.). Rheumatoid arthritis, osteomyelitis, Crohns disease,
Alzheimers disease, and psoriasis are often associated with the syndrome as is renal cell
carcinoma, carcinoma of the urogenital tract, lungs, or gastrointenstinal tract, and Hodgkins and
non-Hodgkins lymphoma (Holmes, 2014, p.3). Also a rare disease, AA is the most common
systemic type of amyloidosis worldwide (Holmes, 2014, p.3). Secondary amyloidosis develops
after long periods of infection or inflammation that produces a long standing increase in the
acute phase reactant protein serum amyloid A or SAA (Pinney & Hawkins, 2012, p. 235). The
AA portion of the protein becomes abnormal, producing fibrils that are then deposited into
tissues; thus, the name AA amyloidosis (BU Amyloidosis Center, n.d.). Secondary amyloidosis
predominately affects the kidneys, but can also be found in the liver and spleen (Amyloidosis
Foundation, n.d.). Symptoms of secondary amyloidosis are kidney failure, gastrointenstinal
complications, fatigue, and edema (Amyloidosis Foundation, n.d.).
Familial amyloidosis or ATTR is also sometimes referred to as hereditary amyloidosis.
Familial types of amyloidosis are exceedingly rare; however the most common type is ATTR
(Pinney & Hawkins, 2012, p. 236). Familial amyloidosis is caused by a mutation in the
transthyretin (TTR) gene which in turn then produces abnormal TRR proteins (BU Amyloidosis
Center, n.d.). There are over 100 known mutations of the TTR protein most of which cause
amyloidosis, however, even normal TRR proteins can cause fibrils (Amyloidosis Foundation,
n.d.). Interestingly, familial amyloidosis is an autosomal dominant inherited disease which

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means that a child of an infected parent has a 50 percent chance of inheriting the disease.
Although the abnormal gene is making the amyloid protein from birth, amyloids deposits do not
begin until mid-life (Amyloidosis Foundation, n.d., tab 3, p. 4, para. 1). ATTR most commonly
presents as cardiomyopathy due to amyloid deposits in cardiac tissue, but can also be found in
the central nervous system, viscera, gut, and vitreous humor (Pinney & Hawkins, 2012, p. 236).
Since ATTR most commonly affects the heart and nervous system the signs and symptoms are
most often neuropathy, dizziness upon standing, cardiomyopathy, and vitreous opacities
(Amyloidosis Foundation, n.d.).
Localized amyloidosis can be a manifestation of various types of precursor proteins that
also cause primary, secondary, and familial amyloidosis. Localized amyloidosis, or ALoc, is
extremely rare with AL type being the most prominent (Pinney & Hawkins, 2012, p. 231). The
most common anatomical sites for amyloid deposits are the respiratory tract, orbits, urogenital
tract, and skin (BU Amyloidosis Center, n.d.). One of the fascinating aspects of localized AL is
the immunoglobulin light chains that create fibrils are produced locally by monoclonal B-cells
rather than the bone marrow as is the case with systemic AL (Pinney & Hawkins, 2012, p. 231).
Localized AL is the type of amyloidosis seen in Patient R and the fact it presented in
subcutaneous tissue made it incredibly rare. Other more prominent types of localized
amyloidosis are Alzheimers disease and Downs syndrome both as a result of irregular amyloids
Beta precursor protein (Holmes, 2014, p. 5). The accumulation of these proteins causes plaque
build-up in both the cerebral cortex and in the blood vessels of the brain leading to increasing
cognitive decline (Holmes, 2014, p.5). Another form of localized amyloidosis is found in
diabetics at the site of insulin injections (Pinney & Hawkins, 2012, p. 231).

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The definitive test for amyloidosis is a tissue biopsy. Historically, a rectal biopsy was the
leading site for the procedure, but through clinical advancements it has become accepted that the
capillaries in subcutaneous fat are often affected in those with amyloidosis (Holmes, 2014, p. 8).
This discovery has made the process of needle aspiration easier for the physician and much less
invasive for the patient. Typically the sample is taken from the abdominal fat pad which can
yield close to a 90 percent sensitivity rate versus 73-84 percent for rectal mucosa (Holmes, 2014,
p.8). The collected tissue is then stained with Congo red dye which colors the amyloids red, then
turning them a characteristic apple green when viewed under crossed polarized light (Pinney &
Hawkins, 2012, p. 230).

Imagekid.com
Cardiac biopsy showing characteristic histological staining using Congo red.
There are times when a firm diagnosis cannot be determined by a subcutaneous fat biopsy. In
these instances, an organ biopsy is required. According to Holmes (2014), an advantage to performing a
biopsy of an involved organ is that it definitively establishes a cause- and- effect-relationship between the

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organ and dysfunction and amyloid deposition (p. 8, para. 8). Once a definitive diagnosis has been
obtained, it is necessary to determine which type of amyloidosis the patient is suffering from. This is
often done through immunostaining. Immunostaining will identify the type of protein the amyloid
consists of leading to a correct diagnosis and proper treatment (Holmes, 2014, p. 8).
Diagnostic imaging can also play a role in the diagnosis of amyloidosis. Cardiac cases are often
diagnosed with the assistance of echocardiograms, cardio magnetic resonance imaging with contrast, and
gated MRIs (Pinney and Hawkins, 2012, p. 231). Nuclear medicine tests such as scintigraphy and PET
scans are helpful when analyzing structure and function of the amyloid deposits and the tissues theyve
invaded (Holmes, 2014, p.8).
The treatment modality used for amyloidosis is often tailored to the individual patient based on
their type of disorder and any underlying or concurrent morbidities. Treatment can range from organ
transplants to chemotherapy to stem cell transplants, often with little success. For those patients with AL
the standard treatment to date has been chemotherapy using melphalan combined with steroids
(Cancer.net, n.d.). It is also recommended these patients undergo an autologous peripheral blood stem
cell transplant in hopes their bone marrow will begin to produce healthy cells (BU Amyloidosis Center,
n.d.). For those patients suffering from AA, the goal of treatment is to control the underlying
inflammation or infection thats causing the disorder. This can also be accomplished through the use of
medical interventions such as chemotherapy or other medications, but is often achieved through surgical
procedures such as organ transplants or resections (BU Amyloidosis Center, n.d.). Familial amyloidosis
has historically been treated through liver transplantation. This is because the mutated TTR protein is
produced in the liver (Amyloidosis Foundation, n.d.). The liver transplant stops the production of
abnormal TTR cells which in turn halts the progression of some TTR disorders (Amyloidosis Foundation,
n.d.). Localized amyloidosis is so rare there is no standard of treatment. Disease management has ranged
from radiation therapy to surgical resection to laser ablation; and if the patient is asymptomatic the
physician may take the watch and wait approach (Pinney & Hawkins, 2012, p. 231). When conducting

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10

my research I was not able to find a single article on radiation therapy and the treatment of amyloidosis.
Before treating Patient R, I know her radiation oncologists also had this problem. There is just no
literature to support this treatment modality. With that said, there is very little written outside the use of
chemotherapy for these disorders.
I believe its important to mention that all of the above mentioned treatments do not cure
amyloidosis nor do they shrink or reduce the number of fibril deposits already found in the body.
The point of these treatments is to slow or inhibit the progression of the disease, but the results have not
been promising. To that end, researchers are currently focused on developing treatments to prevent or
remove fibril deposits using immunology and biologics. Worldwide, there are numerous clinical trials in
various stages of completion exploring new drug therapies and many investigating the use of monoclonal
antibodies (Holmes, 2014, p. 11).
Conclusion
Amyloidosis embodies a wide range of multisystemic diseases. Although understanding of this
disease and its proliferation has only recently made advances, these breakthroughs will no doubt help to
bring about innovative and more effective treatments. This along with better tools to monitor patients and
manage their symptoms will hopefully bring a chance for a healthier and brighter future.

References

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Amyloidosis foundation. (n.d.). Retrieved December 26, 2014, from Amyloidosis Foundation
website: http://www.amyloidosis.org/index.html
Amyloidosis. (2013, July 20). In Cancer.net. Retrieved December 26, 2014, from American
Society of Clinical Oncology website: http://www.cancer.net/cancertypes/amyloidosis/overview
Amyloidosis. (2014, July 29). In Mayo clinic. Retrieved December 26, 2014, from Mayo
Foundation for Medical Education and Research website:
http://www.mayoclinic.org/diseases-conditions/amyloidosis/basics/definition/con20024354
BU amyloidosis center. (n.d.). Retrieved December 26, 2014, from Boston University, Boston
Medical Center website: http://www.bu.edu/amyloid/
Holmes, R. (2014, November 26). Amyloidosis. In Medscape. Retrieved December 26, 2014,
from WebMD LLC website: http://emedicine.medscape.com/article/335414overview#aw2aab6b3
Pinney, J., & Hawkins, P. (2012). Amyloidosis. Annals of clinical Biochemistry, 49, 229-2411.
doi:10.1258/acb.2011.011225

Jill,

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You chose a very interesting disease that is extremely complicated to treat. You
explained the disease well and have a well-written paper.
You did not include details specifying the role of the RT in managing the disease, but the
rest of your paper is impressive. I love that you included an explanation of the three types of
amyloidosis for clarification and understanding for the reader. It is such a rare disease that your
approach is much needed and appreciated. Great job!