amyloid .cardiac amyloidosis. Pathogenetic steps in the development of amyloid diseases.AL amyloidosis. ATTR amyloidosis.ATTRwt amyloidosis. Potential for misdiagnosis of amyloidosis

1. Magdy El-Masry
Prof. of Cardiology
Tanta University

2. Amyloid
Rudolph Virchow in 1854 adopted the term
“amyloid” to refer to tissue deposits of
material that stained in a similar manner to
cellulose when exposed to iodin
Amyloid has blue staining with iodine .
(Virchow 1854)
Cellulose (amylum) has the same staining.

3. (a) H and E stain showing
extensive amyloid
infiltration of the
myocardium (light
pink) which distorts and
separates the myocytes
(darker pink).
(b) Staining with Sulfated
Alcian Blue (another patient)
shows typical amyloid
staining with turquoise
staining of the amyloid
and yellow myocyte staining.

4.  The amyloidoses are a diverse group of
disorders whose effects are felt in every part
of the body and every corner of the globe.
 The hallmark of these diseases is the
aggregation and deposition of misfolded
protein as insoluble amyloid fibrils.
Amyloidosis
A protein misfolding disease

5. The two most common forms of cardiac amyloidosis are the AL and ATTR types.
Pathogenetic steps in the development of amyloid diseases.

6. Inherited mutations in transthyretin cardiac amyloidosis (ATTR) or the
aging process in wild-type disease (ATTRwt) cause destabilization of
the transthyretin (TTR) protein into monomers or oligomers, which
aggregate into amyloid fibrils. These insoluble fibrils accumulate in the
myocardium and result in diastolic dysfunction, restrictive
cardiomyopathy, and eventual congestive heart failure
Pathogenetic steps in the development of amyloid diseases.

7. AL amyloidosis
A : Amyloid fibril protein >>> derived from immunoglobulin light (L) chains
ATTR amyloidosis
A : Amyloid fibril protein >>> derived from the plasma protein transthyretin ( TTR )
ATTRwt amyloidosis
Wild-type ATTR
ATTR V30M amyloidosis
Where the normal valine residue at position 30 has been substituted with methionine.

8. Some types of amyloid have a greater predilection
for the heart than others.
The two most common forms of cardiac amyloidosis are the AL
and ATTR types.
AL amyloidosis may involve almost any other organ in the
body, whereas inherited ATTR amyloidosis variably involves
the heart and autonomic and peripheral nerves.
Nonhereditary ATTR amyloidosis has almost exclusively a
cardiac phenotype.
The commonly diagnosed types of cardiac amyloidosis

9. The commonly diagnosed types of cardiac amyloidosis
Primary (AL) ATTRwt
(Senile CA)
ATTR V122I ATTR T60A ATTR V30M
Precursor/
amyloidogenic
protein
Monoclonal
Immuno-
globulin
light chain
Wild-type
transthyretin
Variant
transthyretin
Variant
transthyretin
Variant
transthyretin
Average age at
presentation
60–70 years 70–80 years ≥60 years ≥60 years 30–40 or 50–
60
years
Common
ethnicity
Any Caucasian African/
Caribbean
Caucasian
(Irish
Any
(Portuguese,
Swedish,
Japanese

10. Primary (AL) ATTRwt
(Senile CA)
ATTR V122I ATTR T60A ATTR V30M
Frequency of
cardiac
involvement
40–50% Almost 100% Almost 100% Detectable in
at least 90%
Uncommon
Other
systemic
involvement
Kidney, liver,
soft
tissue,
nerves,
spleen
Carpal
tunnel
(bladder,
spine)
Carpal
tunnel
Nerves Nerves
The commonly diagnosed types of cardiac amyloidosis
AL, monoclonal immunoglobulin light chain amyloidosis;
ATTR, transthyretin amyloidosis;
ATTRwt; transthyretin amyloidosis associated with wild-type transthyretin;
SCA, senile cardiac amyloidosis

11. Famous People with Amyloidosis

12. A constant complaint of patients with rare diseases is the long
delay between the first symptom and the clinical diagnosis made
by physicians.
This is also true for amyloidosis and can be explained in part by the
great number of organs and systems that can be affected by
amyloid deposits leading to a large variety of symptoms, none of
them being specific of the disease.
Virtually all organs can be affected by amyloidosis.
Clinical Diagnosis
Amyloidosis as a Great Masquerader

13. Potential for misdiagnosis:
physician- and disease related factors

15. Factors leading to misdiagnosis
 Fragmented knowledge among different
specialties and subspecialties
 Shortage of centres and experts dedicated to
specialised disease management
 Erroneous belief it is an untreatable disease
Physician-related factors

16. Factors leading to misdiagnosis
 Common misconceptions about diagnosing and
typing amyloid
• Low voltage is not sensitive nor specific finding in
isolation to exclude the presence of CA
• Serum protein electrophoresis is not a sufficient
screening test to exclude the presence of a plasma
cell disorder that can cause AL amyloid
• A fat pad biopsy has a sensitivity for AL amyloid of
70 % at best and is positive in<50 % of subjects with
ATTR CA
Physician-related factors

17. Factors leading to misdiagnosis
Disease-related factors
 Rarity
 Intrinsic phenotypic heterogeneity
 Genotypic heterogeneity in ATTR
 Necessity of target organ tissue histological
diagnosis in the vast majority of cases

18. Main known determinants of
phenotypic heterogeneity in ATTR.

19. Genotype–phenotype correlation in ATTR.
Some mutations are associated with both neurological and cardiac
manifestations, whereas others lead to an exclusively neurological
disease and a small number are associated with an exclusively
cardiological phenotype.

20. Caveats and pearls in cardiac amyloidosis
• A definite diagnosis of cardiac amyloidosis requires
not only tissue biopsy proof of amyloidotic infiltration
but also the identification of the precursor protein
causing amyloid (since treatment strictly depends upon
aetiology)
• A high index of suspicion is mandatory for the
recognition of CA in the clinical arena (e.g. if you don’t
think of it, you won’t diagnose it!)

21. Caveats and pearls in cardiac amyloidosis
• Cardiac amyloid should be suspected in any patient
with heart failure, unexplained increased LV wall
thickness and non-dilated LV
• In a patient with an initial diagnosis of HCM, look for
the infiltrative phenotype hidden beneath the
hypertrophic one!

22. Caveats and pearls in cardiac amyloidosis
• A distinctive sign of CA is the abnormal ratio between
LV thickness and QRS voltages rather than low QRS
voltages alone.
The absence of low QRS voltages does not rule out a CA
if the context is otherwise fitting and up to 20 % of subjects
with CA can have ECG evidence of LV hypertrophy

23. Caveats and pearls in cardiac amyloidosis
• In an elderly man with unexplained concentric LV
hypertrophy, especially in the absence of hypertension,
always consider the possibility of wild-type TTR CA!
• CA in an elderly patient with monoclonal gammopathy
is not necessarily related to AL: consider the possibility
of wild-type TTR +MGUS (monoclonal gammopathy of
uncertain significance)

24. Caveats and pearls in cardiac amyloidosis
• Longitudinal LV function can be severely
depressed despite a normal LV ejection
fraction and the myocardial contraction
fraction are often low suggesting reduced
global myocardial shortening
• Myocardial deformation is reduced in CA,
but the apex is generally spared

25. Caveats and pearls in cardiac amyloidosis
• In CA, LGE (late Gd enhancement ) distribution at
MRI is heterogeneous: subendocardial LGE is not the
only diagnostic pattern and the absence of LGE does
not exclude CA
• Bilateral carpal tunnel syndrome in a man with HCM-
like phenotype on echo is highly suggestive of TTR-
related CA

26. Evaluation to
Diagnose ATTR
Diagnostic
pathway to
arrive at a
diagnosis of
ATTR

27. Diagnostic pathway to arrive at a diagnosis of ATTR

30. Emerging Therapies for Transthyretin Cardiac Amyloidosis

31. Emerging Therapies for Transthyretin Cardiac Amyloidosis

32. References
Rapezzi C et al . Cardiac amyloidosis: the great pretender. Heart Fail Rev
2015; 20:117–124
Patel K S & Hawkins P N . Cardiac amyloidosis: where are we today?. J Intern Med
2015; 278: 126–144.
Castano A et al. Emerging Therapies for Transthyretin Cardiac Amyloidosis Could
Herald a New Era for the Treatment of HFPEF. http://www.acc.org/latest-in-
cardiology/articles/2015/10/13/08/35/emerging-therapies-for-transthyretin-
cardiac-amyloidosis
Gertz M A et al . Diagnosis, Prognosis, and Therapy of Transthyretin Amyloidosis. J
Am Coll Cardiol. 2015;66(21):2451-2466