Amyloidosis is a group of protein-folding disorders in which >1 organ is infiltrated by proteinaceous deposits known as amyloid. Amyloid involvement of the heart (cardiac amyloidosis) carries the worst prognosis of any involved organ, and light-chain (AL) amyloidosis is the most serious form of the disease

1. - Dr. Akif A.B

3. AMYLOIDOSIS
 Group of protein-folding disorders in which >1 organ
is infiltrated by proteinaceous deposits known as
amyloid
 The deposits are derived from 1 of several
amyloidogenic precursor proteins, and the prognosis
of the disease is determined both by the organ(s)
involved and the type of amyloid
 Amyloid involvement of the heart (cardiac
amyloidosis) carries the worst prognosis of any
involved organ, and light-chain (AL) amyloidosis is
the most serious form of the disease

4. EPIDEMIOLOGY
 There is a slight male predominance of AL
cardiac amyloidosis
 Disease generally presents from the fifth to
seventh decade, although it may occur at all
ages from the fourth decade onward
 Clinical evidence of cardiac involvement is seen
in 22% to 34% of AL patients

5. AMYLOIDOSIS IN HEART
 Transthyretin amyloidosis (ATTR)
 AL amyloidosis
 Secondary Amyloidosis

7. Light-Chain Amyloidosis (AL or
Primary)
 Caused by the proliferation of an abnormal clone of
plasma cells that overproduce lambda, or less
commonly, kappa immunoglobulin light-chain
usually associated with plasma cell dyscrasia, but
usually not associated with multiple myeloma
 Cardiac involvement in AL amyloidosis almost always
occurs in the setting of another significant organ
involvement, and that isolated cardiac disease is present in
<5% of cases
 Heart disease occurs in one-third to half of AL
patients, and heart failure tends to progress rapidly
once the heart is affected and has a very poor
prognosis

8. AL AMYLOIDOSIS

9. Organ Involvements in AL-
Amyloidosis
 It most commonly affects the kidney,
resulting in nephrotic syndrome, with clinical
cardiac involvement being the second
most common presenting manifestation
 It also affects liver,
peripheral/autonomic nerves, soft
tissue, and the gastrointestinal system
 Cerebral involvement does not occur in AL
amyloidosis

10. Amyloidosis Vs Multiple
Myeloma
 In contrast to myeloma, most patients with AL
amyloidosis have <20% of plasma cells in the
marrow, and the manifestations of the disease
are due to the formation of amyloid from the
abnormal circulating free light chains
 Approximately 5% to 10% of patients with AL
amyloidosis will have evidence of overt
multiple myeloma, and vice vers

11. Transthyretin-associated
amyloidoses (ATTR)
 TTR is a transport protein of thyroid hormone
and retinol (vitamin A); hence, the name,
transthyretin
 These include 2 types of amyloidosis:
 Wild type transthyretin
 Mutated type of transthyretin-associated
amyloidosis (ATTRm)

12. Wild-Type Transthyretin (ATTR)
 Also known as senile systemic amyloidosis
(SSA)
 The main involved organ is the heart
 This type is almost exclusively found in elderly
men (male: female=20:1~50:1) and the
symptoms are slowly progressive

13. Mutated Type Transthyretin
 Also called “familial type of amyloid
polyneuropathy (FAP)”
 This type is caused by mutant transthyretin
produced in the liver
 It affects peripheral/autonomic nerves and the
heart
 Autosomal dominant

14. AL Vs ATTR Amyloidosis
 The pathophysiology of cardiac AL amyloidosis
differs from that of ATTR amyloidosis
 Severity of heart failure in AL amyloidosis is more
severe than in TTR amyloidosis, despite higher left
ventricular (LV) mass in the latter
 Lack of change in standard echocardiographic
parameters after successful hematologic
treatment
 This led to the suggestion that AL amyloidosis might
have both toxic and infiltrative components

15. Infiltration of the
myocardium causes
physical cellular
damage and
restrictive
pathophysiology
Circulating cardiotoxic
light chains produce
cellular damage
through various
pathways
In other forms of
cardiac amyloid, such
as TTR, the sole
mechanism of cardiac

16.  It appears that there are different deposition
patterns in TTR and AL amyloidosis
 Predominance of diffuse peri-cellular,
endocardial, and arterial and/or arteriolar
deposits in AL amyloidosis and nodular
deposits in ATTR

17. Secondary amyloidosis
 This type of amyloidosis is caused by serum amyloid
A and also called AA amyloidosis
 It is seen in association with juvenile or adult
rheumatoid arthritis and other rheumatic disorders
such as ankylosing spondylitis, as well as with
inflammatory bowel disease
 Hepatic and renal amyloid deposition dominates
the clinical features, and clinical heart disease
related to cardiac amyloidosis is rare
 Treatment is to heal the underlying inflammatory
process

19. MEDIAN SURVIVAL
AL 24months
(6months if HF at
diagnosis)
ATTRwild 57months
ATTRmutated 31months

21.  The nonbranching fibrils of amyloid are
composed not only of fragments of the precursor
protein, but also contain proteoglycans and
serum amyloid P (SAP)
 They are generally extremely resistant to
degradation, although evidence suggests that
amyloid does slowly resorb from the body once
fibrillogenesis has been halted

22.  The amyloid deposits expand the extracellular
space and stiffen the heart without producing
compensatory dilation, which results in a
restrictive pathophysiology involving both
ventricles
 Atrial amyloid infiltration is almost always
present and frequently causes atrial contractile
dysfunction
 Amyloid deposition also occurs on valves and
perivascularly

25.  The most common early
manifestation of cardiac
amyloidosis of any type is
dyspnea on exertion, which
progresses relatively rapidly
 Dyspnea is due to LV diastolic
dysfunction.
 However, the atria, although they
do dilate, are also abnormally stiff,
and likely contribute to dyspnea on

26.  Often followed by peripheral edema and ascites
 Peripheral edema in AL amyloidosis may also be
due to hypoalbuminemia associated with
amyloid-related nephrotic syndrome
 Atrial arrhythmia may be the initial manifestation
of the disease

27.  Atrial infiltration with amyloid deposits results
in atrial dysfunction, and thrombus formation
may occur, even in this setting of sinus rhythm
 Thromboembolism may thus be an early
manifestation of the disease

28. MICROVASCULAR
DYSFUNCTION
 Coronary microvascular dysfunction is ubiquitous in
AL and ATTR CA
 Manifest as angina in the absence of obstructive
coronary artery disease
 Microvascular dysfunction is not limited to the heart,
and occasionally, causes jaw or buttock
claudication, particularly in AL amyloidosis
 Peri-vascular amyloid deposits, as well as
autonomic dysfunction , may account for
microvascular dysfunction, which can be aggravated
by thick walls and high LV filling pressure

29. ADVANCE DISEASE
MANIFESTATIONS
 Exertional syncope
 Most likely due to a low and fixed cardiac output,
can occur, and this has a particularly poor prognosis
 Jaw claudication, leg claudication, and angina
may all occur due to small vessel amyloid
deposition

31.  In AL amyloidosis, signs of the noncardiac
disease are commonly present
 Approximately 10% of patients have
macroglossia, which may vary from obvious
tongue enlargement to subtle tooth indentation
of the tongue

32. MACROGLOSSIA

33.  Periorbital bruising in the setting of heart failure
is almost pathognomonic of AL amyloidosis
 Because it may be subtle, the eyelids should be
inspected for small bruises

34. Spontaneous Periorbital
Bruise

35. NAIL DYSTROPHY

37.  Jugular venous pressure frequently reveals an
inspiratory rise (Kussmaul sign), a sign that is
shared with patients with constrictive pericarditis
 Unlike severe heart failure caused by most other
etiologies, a third heart sound is uncommon in
cardiac amyloidosis, as is a fourth heart sound
 Valvular dysfunction due to amyloidosis is rarely
severe, although on occasion, tricuspid
regurgitation can be severe

38.  Hepatomegaly usually reflects congestion, but
an enlarged liver may also be due to amyloid
infiltration in patients with AL amyloidosis
 When hepatic infiltration occurs, the liver is
hard and nonpulsatile, and quite distinct from
the congested liver of heart failure

39.  Nephrotic syndrome is a common manifestation
of AL amyloidosis
 It is a clinical clue to the presence of
hypoalbuminemia in a patient with anasarca is
extensive edema in the absence of an elevated
jugular venous pressure

40. Blood Pressure
 The blood pressure in suspected cardiac
amyloidosis is frequently low, due to a
combination of reduced cardiac output and low
peripheral tone
 It should always be measured both supine and
standing, because autonomic nervous system
dysfunction may manifest as significant
postural hypotension

41. PERIPHERAL NEUROPATHY
 Peripheral neuropathy is also a feature of both
AL amyloidosis and familial TTR amyloidosis
 It is symmetric, predominantly sensory, and
may be missed if the neurological examination
is performed casually

42. Carpel Tunnel Syndrome
 Numbness and pain in the hands may be due to
carpal tunnel syndrome, and a history of surgery
for carpal tunnel syndrome may precede the
onset of heart failure by 7 or 8 years
 Commonly associated with ATTR wild type

44. When to suspect Amyloidosis
?
 Non-diabetic nephrotic syndrome
 Non-ischaemic cardiomyopathy with an
echocardiogram showing 'hypertrophy'
 Hepatomegaly or alkaline phosphatase elevation
without imaging abnormality
 Peripheral neuropathy with MGUS or CIDP with
autonomic features
 Atypical myeloma with monoclonal light chains and
modest marrow plasmacytosis

45. Laboratory Radiological
Serum and urine Immunofixation ECG
Serum free light chains ECHO
Biopsy (HPE) Cardiac MRI
Mass Spectrometry
Serum troponin, B-type
natriuretic peptide, and beta-2-
microglobulin should be performed
in all patients
as they provide prognostic
information.

50.  Cardiac amyloidosis is a condition in which the
extracellular space of the heart is expanded by an
amorphous, fibrillar proteinaceous material known
as amyloid

51. Sulfated Alcian Blue
Amyloid
deposits are
extensive and
extracellular,
compressing the
cardiomyocytes
This leads to
myocardial
dysfunction, due
to both stiffening
of the
extracellular
space and direct
myocyte
damage

52. The inset on the
right shows
amyloid
surrounding a
small vessel
This can result
in angina with
normal-
appearing
epicardial
coronary arteries
seen on
coronary
angiography

53. WHAT IS THE GOLD STANDARD
FOR THE DIAGNOSIS OF CA?
 Congo red staining of amyloid deposits showing
apple-green birefringence under polarized light
is the definitive way of determining the presence
of amyloid in tissue
 This test does not determine the type of
amyloid

54. Congo red stained section showing apple green birefringence of amyloid-like
material (A-Amyloid material showing apple green birefringence, C-Connective
tissue separating overlying epithelium-E)

55. Fat Pad Biopsy Sensitivity
Type of Amyloidosis Sensitivity
AL 84%
ATTRwild 15%
ATTRmutated 45%

56.  Once amyloid deposits are found, typing is most
accurately characterized (>98% sensitivity) by
mass spectrometry

57. ECG in Amyloidosis
Electrocardiogram showing very low limb lead voltage with indeterminate axis and
poor precordial R-wave progression in AL amyloid cardiomyopathy
Coronary angiography was normal, and the echocardiogram showed a thick left
ventricle and no pericardial effusion. This voltage/left ventricular mass
mismatch strongly suggests cardiac amyloidosis

58.  The QRS is said to be low voltage when:
 The amplitudes of all the QRS complexes in
the limb leads are < 5 mm; or
 The amplitudes of all the QRS complexes in
the precordial leads are < 10 mm

60. ECHO in Amyloidosis
 Thick-walled ventricle
 Small left ventricular
chamber volume
 Valve thickening
 Atrial enlargement and
signs of elevated filling
pressures with a restrictive
diastolic filling
 Interventricular septal
thickness of > 12 mm, in
the absence of aortic valve
disease or systemic
hypertension
 RV wall thickness>7mm,
elevated RA Pressure

61. Amyloidosis & LV Hypertrophy
 In either form of cardiac amyloidosis, the
dominant imaging finding is the appearance of
cardiac "hypertrophy
 The "hypertrophy" on imaging represents
amyloid fibril deposition rather than myocyte
hypertrophy/hyperplasia, which explains why
ECG voltages are decreased rather than
increased

67. Tissue Doppler and Speckle
Tracking
 Can assist in differentiation from other causes of
wall thickening, including hypertension and
hypertrophic cardiomyopathy.

68.  Two-dimensional (2D) strain mapping shows
relative preservation of apical function
 Early clue to amyloidosis because it gives rise to a
 ‘bulls-eye’ pattern when the segmental strain is
plotted, which is rare in other cardiomyopathies

69. Cardiovascular magnetic
resonance
 CMR is typically considered in individuals with
echocardiograms that are suspicious but not
typical for amyloidosis or
 Individuals with high clinical suspicion,
irrespective of echocardiogram results (gene-
positive individuals with symptoms or at the age
when disease onset is expected)

70.  Standard CMR sequences for cardiac amyloidosis
include
 cine images in the standard long-axis and short-axis
views to study cardiac structure, systolic function,
calculate LV wall thickness and mass
 late gadolinium enhancement imaging (about 5 min
after injection of gadolinium) in axial, short-, and long-
axis views
 optimal myocardial inversion time is assessed
about 4 min after injection of gadolinium to identify
specific patterns of myocardial nulling in amyloid as
opposed to left ventricular myocardial hypertrophy

74. Scintigraphy with 123I-Labeled
Serum Amyloid P Component
 Amyloid deposits contain amyloid P component, which is
derived from the normal circulating protein SAP
 In patients with amyloidosis, SAP leaves the circulation
and is deposited on the amyloid fibrils, presumably
because of its specific calcium-dependent binding
affinity for them
 Scintigraphy with 123I-SAP produces high-quality images
because a high proportion of the tracer is deposited in
amyloid and retained there for prolonged periods,
whereas circulating SAP that has not been deposited is
rapidly catabolized and excreted
 Retention of SAP in amyloid was highly specific and that
the quantity of Radio-labeled SAP in each tissue correlated
with the amount of amyloid present

76. NUCLEAR SCINTIGRAPHY
 Nuclear Scintigraphy Bone-avid, phosphate-
based isotopes, including 99mTc-PYP
(pyrophosphate) and 99mTcDPD (3,3-
diphosphono-1,2-propanodiacarboxylic acid),
have a specific avidity for ATTR amyloid deposits
 An international consensus document has
confirmed the utility of the bone-avid compounds
for the accurate identification of ATTR
amyloidosis , and differentiation from AL
amyloidosis or other wall thickening diseases

77.  A 99mTc-PYP scan that does not show uptake, or shows
mild uptake (Perugini grade 1), is completely consistent
with AL amyloidosis
 Conversely, a bone scintigraphy scan (99mTc-PYP or
99mTc-DPD) with abnormal uptake (grade 2 or 3), in
combination with a negative plasma cell dyscrasia
evaluation has a specificity and positive predictive value of
100% for diagnosis of ATTR cardiac amyloidosis
 However, TTR genotyping must still be performed to
differentiate wild-type from mutant ATTR cardiac
amyloidosis
 Finally, there is increasing evidence that amyloid specific
positron emission tomography (PET) tracers, including 18-
F florbetapir , and the 11-C Pittsburgh B compound (PiB) ,
can identify cardiac amyloidosis, specifically the AL type

81. Systolic function
Rapid filling
Atrial contraction

87.  Because ATTR amyloidosis is not a malignant
process, chemotherapy has no role
 Although there are no currently approved
disease-modifying medications for ATTR
amyloidosis, multiple agents have been studied
and/or are in late-phase trials
 These include the following:
 Diflunisal
 Tafamidis
 RNA interference approaches

89. Diflunisal
 This nonsteroidal anti-inflammatory drug that is
approved for arthritis pain stabilizes the
tetrameric form of transthyretin
 A randomized trial demonstrated slowing of
disease progression among patients with
polyneuropathy due to mutant ATTR
amyloidosis
 Because nonsteroidal anti-inflammatory drugs
are relatively contraindicated in HF, this is not
likely to be a good option for ATTR
cardiomyopathy.

90. Tafamidis
 This agent is approved in some parts of the world
(Europe and Japan) for mutant ATTR amyloidosis
causing polyneuropathy
 Transthyretin Tetramer stabilisation

91. GUIDELINES

92. RNA interference approaches
 Two agents that work via small-interfering RNA or
RNA interference (decreasing production of
transthyretin by the liver) are in Phase 3 trials for
ATTR amyloidosis, including both polyneuropathy and
cardiomyopathy forms

93.  If heart involvement presents beforehand,
cardiac amyloidosis may progress despite liver
transplantation in some cases

97. Treatment of primary amyloidosis
(AL)
 The goal of treatment for AL is suppression of
the plasma cell clone responsible for the
synthesis of the immunoglobulin light chain
 Interruption of light chain deposition allows the
body to solubilise and eliminate the amyloid
deposit
 This prevents further amyloid deposition,
which would result in progressive organ failure

104. PROGNOSTIC MARKERS

105.  Prognosis in amyloidosis is dependent primarily on the
degree of cardiac involvement and
 In AL amyloidosis, on circulating light-chain levels
 Because chemotherapy options have greatly expanded
in recent years, prognosis for AL amyloidosis has
markedly improved as well, with the life expectancy of
most patients, including many of those with significant
cardiac involvement, measured in years rather than
months
 Prognosis in ATTR amyloidosis is generally better than
in AL amyloidosis, though both forms of the disease still
carry a high annual mortality

107.  Biomarkers can be used for patients with light
chain amyloidosis and transthyretin amyloidosis
for staging and prognosis
 Biomarkers can be used for patients with light
chain amyloidosis to determine disease
progression and response to therapies