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Novel Therapies for Amyloidosis in the Era of RNAi …
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In: Amyloidosis ISBN: 978-1-63485-884-7
Editor: Raquel Watts © 2017 Nova Science Publishers, Inc.
Chapter 3
CLINICAL MANAGEMENT OF AMYLOIDOSIS:
GENETIC COUNSELING AS
AN IMPORTANT COMPONENT
OF THE TREATMENT ALGORITHM
Jennifer Davey
1
, Jen Bevilacqua
2
,
Andrew Hesse
3
and Honey V. Reddi
4,
, PhD,
1
Transgenomic Inc, New Haven, CT, US
2
Bridgeport Hospital, Bridgeport, CT, US
3
Perkin Elmer, Branford, CT, US
4
The Jackson Laboratory, Farmington, CT, US
ABSTRACT
Amyloidosis is a result of the abnormal deposition of ‘amyloid’
resulting in disruption of organ and tissue function, which can be
localized or systemic, with the kidney being most frequently affected.
Clinically, the presence of proteinuria, renal insufficiency, heart failure,
orthostatic hypertension, peripheral neuropathy, or unexplained kidney,
heart or systemic disease is suggestive of amyloidosis. Presentation
includes a spectrum of symptoms varying from asymptomatic to fatigue,
extremity edema, angina, or syncope, which is associated with more
Corresponding author: Honey V. Reddi, PhD, FACMG; 10 Discovery Drive, Farmington, CT
06032. Email: honeyreddi@gmail.com.
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
52
advanced disease, complicating diagnosis, definition of incidence, and
treatment and management. A family history of amyloidosis should
therefore also be considered during evaluation and genetic counseling
should be recommended to all patients with a suspicion for or new
diagnosis of a condition with a potential hereditary cause. Genetic
counseling provides invaluable education and support for families with a
genetic diagnosis even if testing is not the goal of the session. The lack of
specificity in susceptibility to amyloidosis makes it a challenge in terms
of treatment and management, with treatment options varying depending
on several factors, including the type of amyloidosis, possible side
effects, the patient’s preferences, and their overall health.
INTRODUCTION
Protein misfolding results in a rare set of diseases called “Amyloidoses,”
wherein localized or systemic deposition of pathologic insoluble fibrillary
protein termed “amyloid,” disrupts normal function (Blancas-Mejía and
Ramirez-Alvarado, 2013). The type of misfolded protein and the organ or
tissue of deposition determines the clinical manifestations of amyloidosis.
Amyloidosis can be localized (the intracellular and/or extracellular amyloid
deposits occur only in the organ or tissue of precursor protein synthesis) or
systemic (extracellular deposits of precursor protein occur in sites different
from those of expression and secretion). Examples of localized amyloidosis
include neurodegenerative disorders like Parkinson’s, Alzheimer’s, and
Huntington’s disease, while systemic amyloidosis includes primary AL
amyloidosis, secondary AA amyloidosis, hereditary or familial amyloidosis,
senile systemic amyloidosis, and ß
2
-microglobulin/dialysis-related amyloidosis
(Table 1) (Blancas-Mejía and Ramirez-Alvarado, 2013; Real de Asúa et al.,
2014). Clinically, the presence of proteinuria, renal insufficiency, heart failure,
orthostatic hypertension, peripheral neuropathy, or unexplained kidney, heart,
or systemic disease are suggestive of amyloidosis.
Primary AL or systemic AL amyloidosis, which occurs due to deposition
of immunoglobulin light-chain proteins produced by plasma cells in different
disease states as in myeloma or monoclonal gammopathies, is the most
common type of amyloidosis (Pinney et al., 2013; Wechalekar, Hawkins, and
Gillmore, 2008). Secondary (AA) amyloidosis occurs due to the accumulation
of serum amyloid A (SAA) protein, in association with chronic inflammation
or infections - e.g., tuberculosis - or inflammatory illnesses such as rheumatoid
arthritis and is the most common type of amyloidosis worldwide, particularly
Clinical Management of Amyloidosis
53
in developing countries. Sustained abnormally high levels of SAA, which is
usually present at low levels in serum, are essential for the development of
amyloidosis, although only a small number of patients with inflammatory
conditions will eventually develop amyloidosis (Obici, Perfetti, Palladini,
Moratti, and Merlini, 2005). Familial or hereditary amyloidosis is the third
sub-type of amyloidosis that occurs due to the deposition of a genetically
defective amylogenic protein such as transthyretin (TTR), A
1
-apolipoprotein,
gelsolin, fibrinogen, lysozyme, etc. (Benson, 2003). Other minor forms of
amyloidosis include senile systemic amyloidosis (SSA), which occurs due to
deposition of normal or wildtype transthyretin, and dialysis-related
amyloidosis (DRA) that occurs as a chronic complication of long-term (>10
years) hemodialysis (Floege and Ketteler, 2001). In DRA, the patient loses the
ability to clear β2-microglobulin, the light chain of the major
histocompatibility complex (HMC) class I molecule, leading to a 60-fold
increase in β2 m serum concentration (Pepys, 2006).
Incidence and occurrence of amyloidosis is difficult to precisely define
since the disease is often undiagnosed or misdiagnosed. The National Health
Service National Amyloidosis Centre in the UK estimated a global incidence
of amyloidosis in England of five cases per million person-years (Pinney et al.,
2013). The age-adjusted incidence of AL amyloidosis in particular is estimated
to be 5.1 to 12.8 per million person-years, inferring that approximately 2,200
new cases occur annually in the United States (Kyle et al., 1992). Prevalence
estimates of primary amyloidosis are clouded by the 10-15% observed
comorbidity with multiple myeloma (Kyle and Gertz, 1995). Of the familial
amyloidosis cases, transthyretin-related amyloidosis (ATTR) accounts for
>90% of cases (Benson, 2005). Though the incidence of ATTR amyloidosis
itself is unknown, it is less common than AL amyloidosis, with the number of
diagnosed cases in referral centers representing 10-20% of the number of cases
of AL amyloidosis (Falk, Comenzo, and Skinner, 1997).
Table 1. Types of Systemic Amyloidosis
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
54
CLINICAL ASPECTS
Clinical presentation includes a spectrum of symptoms varying from
asymptomatic to fatigue, extremity edema, angina, or syncope, which is
associated with more advanced disease. The kidney and heart are the organs
most commonly affected. Amyloid deposition in the kidneys can cause
nephrotic syndrome as a result of reduction in the kidney’s ability to filter and
hold on to proteins. Amyloid deposition in the heart can cause both diastolic
and systolic heart failure.
Primary AL amyloidosis presents as a heterogeneous phenotypic spectrum
including nephrotic-range proteinuria with or without renal dysfunction,
hepatomegaly, congestive heart failure, and autonomic or sensory neuropathy,
making initial diagnosis difficult (Sanchorawala, 2006). In approximately 10%
of patients, amyloid deposition occurs in the renal vasculature or
tubulointerstitium, which causes renal dysfunction without significant
proteinuria. Restrictive cardiomyopathy from amyloid deposition in the heart
leads to rapidly progressive heart failure. Low voltage on the
electrocardiogram, often associated with pseudoinfarct pattern, is found in
many patients. Both congestion from right heart failure and amyloid
infiltration of the liver commonly results in hepatomegaly (Sanchorawala,
2006). Average age observed is 65 years or older, with <10% of cases being
50 years or younger and a great proportion of men than women being affected
(Desport et al., 2012).
Secondary AA amyloidosis occurs during chronic inflammatory disease
(of infectious and noninfectious causes), hereditary periodic fever, and with
certain cancers such as Hodgkin’s lymphoma and can drive pathogenesis of
chronic inflammatory diseases – e.g., rheumatoid arthritis and atherosclerosis.
Primary organs affected are kidney, spleen, and liver. SAA protein is produced
in the liver, activates the immunosome cascade, and functions in immune
modulation (Eklund, Niemi, and Kovanen, 2012). SAA is an acute-phase
serum reactant produced in response to inflammation, with acute -phase levels
>1000-fold compared with non-inflammatory state concentrations (Artl,
Marsche, Lestavel, Sattler, and Malle, 2000).
Hereditary or familial amyloidosis occurs due to autosomal dominant
mutations in several amylogenic genes, with mutations in the transthyretin
(TTR) gene being the most common, accounting for ~90% of hereditary
(familial) amyloidosis (Reddi et al., 2014). The remaining 10% of hereditary
amyloidosis occurs due to mutations in non-TTR genes such as APOA1 (A
I
-
apolipoprotein), APOA2 (A
II
-apolipoprotein), FGA (fibrinogen), GSN
Clinical Management of Amyloidosis
55
(gelsolin), LYZ (lysozyme), CST3 (cystatin C), and LECT2 (leukocyte cell-
derived chemotaxin 2) (Abrahamson, Grubb, Olafsson, and Lundwall, 1987;
Mereuta et al., 2014; Reddi et al., 2014).
Familial transthyretin amyloidosis (h-ATTR), earlier known as familial
amyloid polyneuropathy (FAP), is primarily characterized by a slowly
progressive peripheral sensorimotor neuropathy, as well as non-neuropathic
changes of cardiomyopathy, nephropathy, vitreous opacities, and CNS
amyloidosis. The disease is seen to occur in adults 50 years or older, with a
significant majority being men. Sensory neuropathy starts in the lower
extremities with tingling of hands and feet, followed within a few years by
motor neuropathy. Cardiac amyloidosis is mainly characterized by progressive
cardiomyopathy. Leptomeningeal amyloidosis presents with CNS findings
such as dementia, psychosis, visual impairment, headache, seizures, motor
paresis, ataxia, myelopathy, hydrocephalus, or intracranial hemorrhage
(Sekijima, Yoshida, Tokuda, and Ikeda, 2012). About 100 mutations have
been identified in TTR (Hawkins et al., 2015) with V30M primarily associated
with neuropathy, T60A neuro/cardio, and V122I associated exclusively with
cardio (Reddi et al., 2014). The V122I variant is common in African
Americans, with a heterozygote frequency of 4% and homozygous V122I
associated with 10 year decrease in age of onset in African American in
seventh decade of life (Reddi et al., 2014). The age-related form (senile
systemic amyloidosis (SSA)/wt-ATTR) affects men 25 to 50:1 after 75 years
of age.
The non-TTR amyloidoses are rare and by-and-large do not cause nerve
damage. In general, they present with high blood pressure and kidney disease
in middle-age. The liver or heart can sometimes be affected. Of non-TTR
mutations, the FGA variant E526V is most common, and generally presents
with kidney disease after the age of 50 and leads to complete kidney failure
within a few years. Mutations in APOA1 and LYZ have been associated with
slower progressing renal impairment; laryngeal involvement was noted in one
patient with a variant in APOA1. Less than 30 families with mutations in these
three genes have been identified (Lachmann et al., 2002). Gelsolin-associated
amyloidosis (AGSN) is extremely rare, occurs mainly in Finland, and is also
known as Familial Amyloidosis Finnish type (FAF) (Solomon, Page, Balch,
and Kelly, 2012). Cystatin C has one variant known to be associated with
complications of cerebral hemorrhage (Abrahamson et al., 1987). LECT2-
associated amyloidosis has been recently described (Mereuta et al., 2014). The
amyloid precursor protein is a blood protein called leukocyte cell-derived
chemotaxin 2 (LECT2). Mutations in the LECT2 gene that may lead to LECT2
Jennifer Davey, Jen Bevilacqua, Andrew Hesse et al.
56
amyloidosis have not yet been identified. Patients with this condition always
have kidney problems, but they may also have amyloid deposits in the adrenal
glands, spleen, and liver.
DETECTION AND DIAGNOSIS
The systemic amyloidoses share many non-specific symptoms making
their diagnosis difficult. As elucidated above, even the more organ-specific
symptoms such as swelling due to kidney or heart involvement, tingling in
fingers and toes due to nerve involvement, or breathlessness due to cardiac
involvement are too non-specific to clearly define diagnosis with all too often
organ dysfunction being advanced by time of correct diagnosis (Sanchorawala,
2006). Standard of testing for a suspicion of amyloidosis requires
identification of amyloid in tissue using Congo red staining for specific apple
green birefringence using polarizing microscopy techniques. Non-invasive,
fine needle aspiration (FNA) sample collection in abdominal fat is a simple
procedure that tests positive for amyloid deposits in 70% of patients with AL
amyloidosis. Other relatively non-invasive tissues for testing include the
salivary glands, gingiva, rectum, and skin; however, tissue biopsy from an
affected organ may be necessary to establish an accurate diagnosis
(Sanchorawala, 2006).
A diagnosis of AL amyloidosis should be considered in patients with
unexplained proteinuria, cardiomyopathy, neuropathy, or hepatomegaly and in
patients with multiple myeloma that has atypical manifestations. Confirmation
of diagnosis requires identification of plasma cell dyscrasia by detection of the
abnormal monoclonal light-chain in blood serum or urine via immunofixation
electrophoresis. After serum or urine detection, bone marrow biopsy is still
needed to determine plasma cell burden and for differential diagnosis to rule
out multiple myeloma (Swan, Skinner, and O’Hara, 2003). In patients with
chronic inflammatory disorders, the most frequent and differentiating clinical
manifestations to indicate AA amyloidosis testing are proteinuria leading to
nephrotic syndrome and renal insufficiency (Real de Asúa et al., 2014). As
much as 95% of AA amyloidosis patients present with proteinuria, and this co-
occurrence has prognostic implications (Lachmann et al., 2007). Histological
staining using Congo red is used to confirm presence of amyloid and
demonstration of clinical organ involvement.
However, since the clinical management of amyloidosis is based on the
treatment of the underlying etiology, the accurate identification of the protein