Michael Polydefkis, MD, prepared hereditary ATTR amyloidosis infographics for this CME activity titled, "Clinical Pearls for the Accurate Diagnosis and Optimal Treatment of Hereditary ATTR Amyloidosis." For the full presentation, monograph, complete CME information, and to apply for credit, please visit us at http://bit.ly/2W4dPOW. CME credit will be available until July 10, 2020.

1. Identifying hATTR Amyloidosis: A Rare, Inherited, Rapidly Progressive, and Life-Threatening Disease
Main Types of ATTR Amyloidosis1, 8-12
What Is Amyloid TTR
(ATTR) Amyloidosis?1-4
Pathophysiology1,5
Amyloidosis
Characterized by extracellular deposition of
toxic, insoluble, cross β-sheets within various
locations in the body, causing disruption and
dysfunction of the normal surrounding tissue
?
proteins known to form amyloid, of which
TTR is one>30
Transthyretin (TTR)
127-amino-acid protein primarily
synthesized in the liver, forms a
tetrameric, 55 kDa transport protein
Diagnostic Hurdles & Red Flags1,6
Most common presentations with cardiac/
neurologic involvement can mimic other
diseases at early stages, eg, LVH, which
has an expansive differential diagnosis
Misdiagnosis and delayed diagnosis
are common
Certain red flags exist for which it is important
to consider a diagnosis of ATTR
Confirming hATTR Amyloidosis in Patients Who Present With1,6,12
:
Clinical Manifestations6,7
Val30Met
Thr60Ala
Val122Ile
MutationHereditaryWild type Polyneuropathy Cardiomyopathy
Complete neurologic examination Cardiac examination
Genetic analysis to determine presence of pathologic mutation
Tissue biopsy + Congo red staining
Identification of amyloid protein
TTR tetramers TTR monomers Misfolded TTR Amyloid deposits
Secreted
by liver
Destabilized
tetramers
dissociate
into monomers
Monomers
misfold and
aggregate into
amyloid fibrils
Fibrils
deposited
at multiple
sites
Neurologic Cardiovascular GI Ocular Nephropathy Carpal tunnel syndrome
Clinical Pearls for the Accurate Diagnosis and Optimal Treatment
of Hereditary ATTR Amyloidosis
Full references, accreditation, and disclosure information available at PeerView.com/HMV930.

2. TTR Suppression12,16-19
TTR Stabilization12,20-22
Molecule
Double-stranded siRNA encapsulated in
a lipid nanoparticle; targets the liver
Mechanism
Knocks down TTR mRNA
Results from the APOLLO trial
∆ 34.0 ∆ 21.1
Safety
Mild-to-moderate AEs in most patients;
most common were peripheral edema
or infusion-related reactions
FDA
approved
Molecule
Antisense oligonucleotide
Mechanism
Knocks down TTR protein production
Results from the NEURO-TTR trial
Safety
A few patients developed thrombocytopenia
and glomerulonephritis; no similar events
with enhanced monitoring
mNIS+7 Norfolk QOL-DN Score
∆ 19.7 ∆ 11.7
FDA
approved
mNIS+7 Norfolk QOL-DN Score
Molecule
1,3-benzoxazole
Mechanism
Binds to TTR tetramer, preventing
dissociation; for ATTR cardiomyopathy
Results from the ATTR-ACT trial
Safety
Well tolerated; similar AE incidences
and types to patients treated with placebo
Molecule
Generically available NSAID
Mechanism
Binds to TTR tetramer, preventing
dissociation; off-label for hATTR
polyneuropathy
Results from the trial
Safety
A few patients developed thrombocytopenia
and glomerulonephritis; no similar events
with enhanced monitoring
∆ 8.7 ∆ 1.5
mNIS+7 SF-36
Physical
Lower
All-cause mortality
Rate of cardiovascular hospitalizations
Rate of decline in timed 6-m walk test
Rate of decline in HF scoring system
∆ 3.7
SF-36
Mental
29.7%
<2-pt
mNIS+7 ↑
Rationale
Majority of TTR is produced by the liver
OS
75% at 5 years for patients with
Val30Met amyloidosis
Limitations
● Availability of organ for transplant
● Mutation-specific outcomes
● Prior organ impairment not reversed
● Disease progression even after transplant
● Long-term post–orthotopic liver transplantation
immunosuppressive therapy required
Orthotopic Liver Transplantation12-15
Current
Approaches
to the Treatment
of hATTR
Amyloidosis
Patisiran
Inotersen
Tafamidis
Diflunisal
FDA
approved
Under
investigation
Clinical Pearls for the Accurate Diagnosis and Optimal Treatment
of Hereditary ATTR Amyloidosis
Full references, accreditation, and disclosure information available at PeerView.com/HMV930.