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Clinical Management of Amyloidosis
57
causing the amyloidosis is of paramount importance (Figure 1). Routinely
used immunohistochemistry and Congo red staining have low specificity and
sensitivity, prompting the recent development of techniques with enhanced
sensitivity and specificity, which use the combination of laser microdissection
(LMD) and the analytical power of tandem mass spectrometry (MS)–based
proteomic analysis (Vrana et al., 2009). An abnormal protein analysis by mass
spectrometry (MS) suggests the presence of a mutation, and based on the type
of amyloid identified, gene sequencing for presence of mutations in the
specific gene is initiated. If no alterations are detected, gene analysis need not
be performed unless the diagnosis is still strongly suspected, which can rule-
out the possibility of a false-negative by MS. For predictive testing in cases
where a familial mutation is known, testing for the specific mutation by DNA
sequence analysis is recommended in at-risk individuals. One has to keep in
mind that if the individual has had a domino transplant, MS could result in
abnormal protein result but no mutation will be identified (Reddi et al., 2013).
Identification of a variant likely associated with disease will need to be
supported by post-test genetic counseling as a part of continued care.
GENETIC COUNSELING FOR HEREDITARY AMYLOIDOSIS
Genetic counseling for hereditary amyloidosis is an important component
of a complete clinical management plan and is helpful for patients needing a
genetic diagnosis as part of continued care and for presymptomatic/predictive
genetic testing. Genetic counseling should be recommended to all patients
with a suspicion for or new diagnosis of a condition with a potential hereditary
cause. A genetic counselor can assist the patient in understanding the
hereditary component of disease and impact on family members. In the setting
of a new diagnosis, the session may focus on collection of a complete family
history and the possibility of genetic testing as a method of identifying the
cause of disease. This discussion often includes detailed information about the
genetic testing process, possible results, and the impact of those results on
clinical care and preparation for familial testing, if applicable. As part of a
multidisciplinary team, a genetic counselor acts as a liaison and provides
support to the patient and at-risk family members who may be interested in
testing for themselves. Familial testing should only follow genetic testing in
the proband (primary affected individual in the family). Since TTR mutations
are inherited in an autosomal dominant pattern, a complete family history can
identify at-risk family members.
LMD = laser microdissection; MS = mass spectrometry; SAA = serum amyloid A; TTR = transthyretin.
Figure 1. Algorithm for detection and confirmation of a diagnosis of Amyloidosis.
Clinical Management of Amyloidosis
59
Figure 2. Pedigree analysis for a suspicion of amyloidosis. Parental testing identified
the familial TTR mutation in the patient’s mother (I-2) whose neuropathy had
previously been misdiagnosed as diabetic neuropathy. This finding clarifies the
patient’s brother’s (II-2) risk for having inherited the mutation as 50% compared
to <1% if the mutation was assumed to be de novo.
Some family members may already be experiencing undiagnosed or
misdiagnosed symptoms and can benefit from early intervention once their
condition is confirmed. Variable expressivity of hereditary amyloidosis,
varying ages of onset, and the potential for a misdiagnosis may cause a
mutation to appear to be de novo, but mutation testing for relatives of a
proband, especially parents if available, can be helpful (see Figure 2 above).
Confirmatory familial genetic testing is appropriate for any and all at-risk
family members who are experiencing related symptoms and should be done
only after a disease-causing mutation has been identified in a proband.
Familial testing should be targeted for the known mutation to ensure validity
of the result. Caution should be taken in arranging testing for any
asymptomatic family members. Extensive pre- and post-test genetic
counseling is important to ensure informed consent is obtained for any
presymptomatic genetic testing in adult family members. Since
presymptomatic genetic testing for hereditary amyloidosis predicts a future
life-threatening disease, pursuing testing is a highly personal decision and can
have major impacts on mental health and familial relationships (Graceffa et
al., 2009; Paneque et al., 2009). Variability exists in the number, duration, and
timing of pre-test genetic counseling sessions, and as no standardized
recommendations have been set, practitioners and/or centers use their best
judgment to set schedules (Obici et al., 2016; Skirton, Goldsmith, Jackson, and
Tibben, 2013). Due to the variable expression of hereditary amyloidosis and
the range and unpredictability of age of onset even within families, pre- and
post-test counseling is complex and should be done with care and guided by
the patient’s primary concerns and motivation. While presymptomatic genetic
testing for hereditary amyloidosis in adults can be done with sufficient
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
60
counseling, like other adult-onset conditions, testing for asymptomatic minors
is not appropriate. The child’s autonomy is violated when the decision for
presymptomatic genetic testing is made by parents or medical professionals
and for that reason is not recommended by medical societies (NSGC, 2012;
Ross et al., Ross, Saal, David, and Anderson, 2013).
Another use for genetic counseling and testing for families with hereditary
amyloidosis is reproductive planning in the form of prenatal testing or pre-
implantation genetic diagnosis. Prenatal testing can be done through
amniocentesis or chorionic villus sampling if the familial mutation has been
identified. As with genetic testing of minors, prenatal testing raises concerns
for loss of autonomy on the part of the child. As an alternative, pre-
implantation genetic diagnosis has been successful in identifying embryos that
do not carry a familial TTR mutation leading to the birth of healthy children
without the familial risk for amyloidosis (Almeida, Costa, Moreira, Gonçalves,
and Braga, 2005).
It should be noted that genetic counseling has value beyond genetic testing
and should be recommended for all at-risk relatives independent of desire for
genetic testing (Figure 3). Genetic counseling provides invaluable education
and support for families dealing with a genetic diagnosis even if testing is not
the goal of the session. At-risk family members who elect not to go foreword
with genetic testing still need accurate and complete information about the
familial condition and can benefit from long term clinical monitoring for early
detection of symptoms. An open conversation and opportunity to build a
relationship with an affected family is important to encourage and support
effective coping strategies, identify individuals who may need benefit from
more intensive mental health counseling, and encourage continuing
communications or re-contact in light of new information (diagnoses, births/
deaths, research, emerging tests, treatments, etc.).
TREATMENT AND MANAGEMENT
Accurate diagnosis is a critical part of the treatment and management of
amyloidosis, as treatment options are type-specific. In cases of localized
amyloidosis, targeted treatments such as excision or laser removal are most
often used (Leung, Nasr, and Sethi, 2012). In cases of primary AL and familial
amyloidosis, treatment becomes much more complicated, as multiple organ
involvement and organ-specific risks hinder aggressive treatments. Those with
secondary AA amyloidosis must reconcile disease management of both their
Clinical Management of Amyloidosis
61
primary condition and amyloidosis, which presents its own set of unique
obstacles. Most common treatments for primary AL amyloidosis and
hereditary amyloidosis include transplantation and chemotherapy, and more
recently, TTR-stabilizing or TTR-lowering agents, as well as monoclonal
antibodies (Table 2).
Transplant for the affected organ is the first line of treatment in most cases
of early stage amyloidosis, though strict eligibility requirements must be met,
disqualifying a large portion of patients (Muchtar, Buadi, Dispenzieri, and
Gertz, 2016). Transplant-eligible patients must have no more than two organs
involved and generally must be less than 65 years old and with no sign of
advanced cardiac involvement (Desport et al., 2012). With the multiple organ
involvement and consequent organ dysfunction in systemic amyloidoses, it is
estimated that 80% of patients are rendered unsuitable for aggressive
treatments such as high-dose chemotherapy with stem cell transplant, and
many can become ineligible when treatment is delayed as disease can progress
rapidly (Kapoor, Thenappan, Singh, Kumar, and Greipp, 2011). In addition to
eligibility requirements that disqualify many patients, transplants carry
substantial risks, particularly for those with cardiac involvement. Autonomic
stem cell transplant (ASCT), used in primary AL amyloidosis, is an attractive
treatment option for those whose presentation has not progressed beyond the
early stage but carries a mortality rate of 7-39%, a rate that increases in cardiac
cases due to higher risk of sudden cardiac death and cardiopulmonary failure
(Kapoor et al., 2011). Those with cardiac amyloidosis have the option of heart
transplant; however, such treatment is controversial, as amyloid can build in
the transplant heart, donor hearts are limited, and it does not address the
extracardiac involvement seen in many patients (Kapoor et al., 2011). Heart
transplant has been found to result in a 5 year survival of only 20-30%;
addition of chemotherapy post-transplant only increased survival to 36%,
compared to a 5 year survival of 67% in patients with transplants for other
cardiac indications (Kapoor et al., 2011).
Because the amyloid precursor protein TTR, which is responsible for most
cases of familial amyloidosis, is produced primarily in the liver, liver
transplant is the first line of treatment for hereditary amyloidosis. This
treatment has proven most successful in patients with the common V30M
mutation, though typical transplant risks and other complicating factors pose
significant challenges. In addition to common transplant risks including post
surgical infection, chronic renal failure, and diabetes (D. Adams, 2000;
Yamamoto et al., 2007), patients with h-ATTR with neurological involvement
face a 1 year mortality rate of 7-25% and a 7.7 fold higher risk of early hepatic
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
62
artery thrombosis (Bispo et al., 2009; Hawkins et al., 2015). It is important to
note that TTR is produced locally in both the eye and central nervous system,
and because even highly destabilized TTR can escape degradation with the aid
of tissue-specific chaperone molecules, liver transplant will not halt disease
progression in these sites (Sekijima et al., 2005). As liver transplant alone in
patients with h-ATTR with cardiac involvement is insufficient, combined liver
and heart transplant is an option, though this treatment has only been used in a
small number of cases and carries substantial risk. Studies have shown it to be
an effective treatment, however, with similar outcomes to isolated heart
transplant for other indications and no recurrence of cardiac amyloidosis
(Nelson et al., 2013).
In those patients with systemic amyloidosis who are not eligible for
transplant, high-dose dexamethasone in addition to oral melphalan (MDex) is
as an effective and well-tolerated treatment (Desport et al., 2012; Palladini et
al., 2004). Additionally, because of its low toxicity profile, it is suitable for
those with advanced disease (Desport et al., 2012). Not only has MDex shown
great efficacy in treating transplant-ineligible patients, a 2007 French multi-
center study found that treatment with MDex resulted in a median survival rate
of 56.9 months versus just 22.2 months for patients who received oral
melphalan followed by liver transplant (Jaccard et al., 2007). Addition of
antimyeloma agents such as thalidomide, lenalidomide, and bortezomib
induces a rapid hematological response in most patients; MDex plus
bortezomib resulted in a 94% hematological response and a complete response
in 60% of patients (Desport et al., 2012). However, reduction of left
ventricular ejection fraction is a risk for those with cardiac involvement, thus
this treatment should be used with caution in such patients.
Secondary AA amyloidosis is often preceded by several years of active
inflammation, and SAA concentration must reach a critical threshold before
there is amyloid aggregation. Thus, monitoring SAA levels in patients with
inflammatory disease is a crucial part of disease management. SAA is
produced mainly in the liver and under the regulation of IL-1. Because of this,
SAA serum level management by use of anti IL-1 receptor antagonists has
been proposed as a possible pathway for treatment. Blockage of the IL-1
system has been an effective and safe treatment in the rheumatogic field;
however, there has been mixed success in treating patients with inflammatory
disease complicated by amyloidosis (Kallianidis, Ray, Goudkade, and de
Fijter, 2016; Scarpioni, Ricardi, and Albertazzi, 2016).
Table 2. Summary of treatment options for Systemic Amyloidosis
Figure 3. Genetic Counseling in the clinical management of Amyloidosis.
Clinical Management of Amyloidosis
65
Recent developments in the treatment of systemic amyloidosis have
focused on targeted stabilization and reduction of amyloid precursor proteins
such as TTR. The investigational treatments tafamidis and diflunisal are
hypothesized to stabilize TTR by interacting with the thyroxine binding site of
the tetramer, thus preventing the aggregation of TTR as amyloid (Hawkins et
al., 2015). Though tafamidis has become a first-line treatment in France, it has
not been granted regulatory approval by the FDA due to inadequate evidence
of effectiveness (David Adams et al., 2012; FDA, 2012). Diflunisal, a non-
steroid anti-inflammatory drug (NSAID) offered off-label in cases of familial
amyloidosis with neuropathy, carries the typical risks of NSAID use, which
can be especially hazardous to patients with amyloidosis, and though the
results of the two year study of its efficacy in treating amyloidosis seem
promising, a significant drop out rate brings into question the validity of the
results. In addition, it is not recommended for patients with cardiac
involvement, as it is less effective and particularly hazardous for that
population (Hawkins et al., 2015). A third stabilizing agent, doxycycline plus
tauroursodeoxycholic acid (TUDCA), is currently under investigation; an
open-label phase II study in which 60% of patients completed the 12 month
treatment resulted in 75% cardiac stability and 46% neurological stability;
treatment was generally well-tolerated by patients (Obici et al., 2012).
Investigational treatments utilizing antisense oligonucleotides (ASO) and
small interfering RNA have been aimed at reducing TTR by site-specific
degradation. Because target sequences are conserved between both mutant and
wild-type TTR, such treatments are suitable for use in both h-ATTR and wt-
ATTR (senile system amyloidosis (SSA)). ISIS-TTR
Rx
, an ASO-based
therapy, reduced protein levels by 80% in mouse and non-human primate
models and was well-tolerated up to 400 mg in healthy volunteers (Ackermann
et al., 2012; Benson et al., 2006). Patisiran (ALN-TTR02) and revusiran
(ALN-TTRsc) reduce TTR levels by inducing the RNAi-silencing complex;
both treatments have shown significant reduction of TTR, achieving ~90%
maximum reduction in patients with h-ATTR with either cardiomyopathy or
neuropathy (Coelho et al., 2013; Zimmermann et al., 2013). When compared
to ASO treatment, revusiran presented at 2-3 log lower levels in the liver and
kidney but achieved superior knockdown (Butler et al., 2010). Both treatments
are currently recruiting patients for phase III studies (Hawkins et al., 2015).
Though TTR stabilizing and lowering treatments appear to be effective in
halting the progression of disease, such approaches do not address existing
amyloid deposits, prompting investigational treatment utilizing anti-SAP
(serum amyloid P) antibodies. SAP is present as a non-fibrillar constituent in
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
66
all amyloid deposits, making it an ideal target for all types of amyloidosis.
Administration of anti-human SAP antibodies to mice with amyloid deposits
containing human SAP has been shown to trigger a potent and rapid clearance
of massive visceral amyloid deposits with no adverse effects (Bodin et al.,
2010). A humanized version of the anti-SAP antibody was used in conjunction
with CPHCP, a drug that depletes circulating SAP, in a phase I study
comprised of 15 patients and was successful in amyloid deposit clearance in
the liver and select other tissues, with no adverse effects (Richards et al.,
2015). Patients with cardiac involvement were not recruited for this study for
safety reasons, so it is unclear whether such treatment is suitable for those
cases.
CONCLUSION
Amyloidosis poses a significant challenge in terms of diagnosis and
treatment, as symptoms are often non-specific, and treatment depends heavily
on amyloid type and organs involved. Congo red staining is the gold standard
for identifying amyloid tissue, and recent development of laser
microdissection (LMD) and tandem mass spectrometry (MS)–based proteomic
analysis has enhanced sensitivity and specificity of amyloid typing. The
addition of genetic testing to diagnostic tools further enhances the specificity
with which amyloid type can be diagnosed. Certain treatments for hereditary
amyloidosis have proven especially effective for specific variants, and thus,
identification of a variant in a patient can have a significant impact on
management of the disease. Pre- and post-testing genetic counseling is
essential to determine appropriate testing and to educate patients of the major
impact results can have on mental health and familial relationships.
REFERENCES
Abrahamson, M., Grubb, A., Olafsson, I., and Lundwall, A. (1987). Molecular
cloning and sequence analysis of cDNA coding for the precursor of the
human cysteine proteinase inhibitor cystatin C. FEBS Letters, 216(2),
229–33.
Ackermann, E. J., Guo, S., Booten, S., Alvarado, L., Benson, M., Hughes, S.,
and Monia, B. P. (2012). Clinical development of an antisense therapy for