AMYLOID

Question 1

Definition of amyloidosis?

Answer 1

Amyloidosis is a categories of diseases classified by extracellular deposition of insoluble fibrillar misfolded proteins in the form of beta-pleated sheets.

Protein deposition leads to organ dysfuncton

Question 2

What is the most important thing to find out in amyloidosis?

Answer 2

The type of precursor protein
This guides management and therapeutics and prognosis

Question 3

Two most common types of amyloidosis?

Answer 3

AL (Light chain)
ATTR

Question 4

Pathophysiology of AL Amyloidosis?

Answer 4

Caused by a hematological process where an abnormal plasma cell clone produes immunoglobulin light chains (Kappa and Lamba) that form amyloid fibrills which deposit in organs

Question 5

Organs affected in AL amyloidosis?

Answer 5

Kidney, heart, liver, CNS, autonomic nervous system, soft tissues and GI tract

Question 6

Two most common organs affected in AL amyloidosis?

Answer 6

Heart (75-80%) and kidneys

Question 7

Mechanisms of cardiotoxicity in AL Amyloidosis?

Answer 7

1) Interstitial or peri-vascular amyloid fibrill deposition leading to destruction of tissue architecture, ischemia and direct myocyte toxicity
2) Light chains cause ROS and apoptosis which is light-chain toxicity

Question 8

Incidence of AL Amyloidosis?

Answer 8

Rare disease, incidence of 1 in 100,000

Question 9

Median age of AL Amyloidosis?

Answer 9

63 years

Question 10

Association of AL Amyloidosis with multiple myeloma?

Answer 10

Most cases of AL don’t have co-existing MM. However, 15-20% cases of MM can have co-existing AL Amyloidosis

Question 11

Association of MGUS and AL Amyloidosis?

Answer 11

in patients with MGUS, only 1% will develop AL Amyloidosis

Question 12

Types of ATTR amyloidosis?

Answer 12

1) Wild type (ATTRwt)
2) variant type (ATTRv)

Question 13

What determines classification or type of ATTR amyloidosis?

Answer 13

Genetics! in ATTRv there is a mutation in the TTR protein itself whereas in ATTRwt there is normal genetics

Question 14

Pathophysiology of ATTR amyloidosis?

Answer 14

TTR also called prealbumin is produced from the liver in a tetramer form but is unstable and breaks down into a monomer of TTR. This then gets misfolded and then forms amyloid fibrills.

Note: TTR (also known as prealbumin) is a circulating transport protein for thyroid hormone and retinol/retinol-binding protein.

Question 15

Genetics in ATTRv ?

Answer 15

For ATTRv disease, the destabilization and misfolding process results from a missense single nucleotide point mutation in one of the inherited TTR alleles (autosomal-dominant inheritance pattern).

Question 16

Nomenclature in ATTRv?

Answer 16

Historical nomenclature for ATTRv disease places a one- or three-letter abbreviation for the normal amino acid at the mutation point in the protein followed by the substituted amino acid (e.g., ATTR V122I signifies isoleucine replacing valine at position 122 in the TTR amino acid sequence).

Question 17

Main genes involved in ATTRv?

Answer 17

There are five main mutations that are implicated in an exclusive, predominant, or frequently occurring cardiac phenotype worldwide: V122I, T60A, V30M (late onset), I68L, and L111M

V122I is the most common mutation in the United States and is prevalent in 3-4% of African Americans. Although this translates into an estimate of >1.5 million persons in the United States as carriers of the V122I allele, the penetrance of the ATTR-CM phenotype is unclear and depends on the age of ascertainment, with greater penetrance with advancing age.

Question 18

ATTR wt pathogenesis?

Answer 18

For ATTRwt disease, the pathobiology of TTR tetrameric destabilization and amyloid fibril formation has not been well elucidated but is related to the aging process. The disease has been most commonly observed in older (>65 years of age), male patients.

Question 19

Clinical symptoms common in AL and ATTR amyloidosis?

Answer 19

There is considerable overlap in the manifestations of AL and ATTR amyloidosis with respect to phenotypic cardiac and nervous system expression.

Both types of amyloid can cause:
1) peripheral sensorimotor neuropathy
2) compressive focal neuropathy with bilateral carpal tunnel syndrome
3) autonomic dysfunction.

Question 20

Clinical presentation more common in AL amyloidosis?

Answer 20

1) Periorbital purpura
2) macroglossia
3) submandibular lymphadenopathy
4) significant weight loss
5) bleeding in the gastrointestinal tract
6) renal failure with nephrotic syndrome

Question 21

Clinical features more common in ATTR?

Answer 21

1) lumbar stenosis (resulting from amyloid deposition in the ligamentum flavum)
2) spontaneous biceps tendon rupture
3) rotator cuff tears
4) total knee and hip arthroplasty

Question 22

Bilateral carpel tunnel syndrome is more common in which amyloidosis?

Answer 22

More common in ATTR (especially wt)

Question 23

ECG findings in amyloidosis?

Answer 23

1) Low voltage QRS: Discordance between expected ECG voltage in the context of increased echocardiographic LV wall thickness. This could be only in the limb leads
2) Pseudo-infarct pattern: Pathological Q waves (1/4th R wave height) or QS complexes

Question 24

Echocardiographic findings in amyloidosis?

Answer 24

1) Biventricular thickening with LV wall thickness > 12 mm especially in absence of other causes
2) Bi-atrial enlargement
3) Inter-atrial septal thickening
4) Speckled appearence of myocardium
5) Increase LA filling pressures
6) Dilated IVC
7) Hypocontractile basal segments with preserved contractility on the apical segments

Question 25

Echocardiographic findings in amyloidosis?
Strain findings?

Answer 25

We can have reduced GLS and apical : basal >2:1 indicative of apical sparing and cherry on top pattern

Question 26

Echocardiographic findings in amyloidosis?
Heart failure?

Answer 26

1) Amyloid CM is commonly associated with heart failure with preserved ejection fraction (HFpEF) and may reflect a causative etiology in a sizable proportion (e.g., 10-15%) of older patients with HFpEF
2) Amyloid may also be a factor in heart failure with reduced ejection fraction (HFrEF) especially in advanced stages given that 10% of the African American patients >60 years of age in the BEST (Beta-Blocker Evaluation of Survival Trial) trial (a randomized trial that tested the efficacy of bucindolol in HFrEF) were found to carry the V122I mutation.

Question 27

Echocardiographic findings in amyloidosis?
Associations?

Answer 27

1) ATTR disease may also mimic hypertrophic cardiomyopathy (HCM), as 25-35% of individuals with ATTRwt-CM demonstrate asymmetric septal thickening; a proportion of older patients with ATTR-CM may indeed be misdiagnosed with HCM
2) ATTR is diagnosed in 6-12% of patients undergoing surgical aortic valve replacement (AVR) and 16% of those undergoing transcatheter AVR. Patients with ATTR-CM are more likely to manifest a low-flow, low-gradient AS phenotype

Question 28

CMR findings in amyloidosis?

Answer 28

CMR imaging with late gadolinium enhancement (LGE) in amyloid CM demonstrates diffuse enhancement throughout the myocardial segments, either in a global subendocardial, patchy, or transmural pattern often with atrial involvement

As extracellular amyloid fibril deposition increases the interstitial space between myocytes, parametric T1 mapping demonstrates increased native (noncontrast) T1 and increased extracellular volume (ECV) fraction typically >0.4

Question 29

Can CMR diagnose amyloidosis?

Answer 29

As with echocardiography, CMR features are highly suggestive but are not in themselves diagnostic of amyloid CM

One distinct advantage of CMR is its capacity to identify other diseases that may mimic the amyloid CM phenotype (e.g., HCM, Fabry disease).

Question 30

Can CMR differentiate between AL and ATTR amyloidosis?

Answer 30

No