ATTR Transthyretin Amyloidosis

Slide 1 · ATTR (Transthyretin) Amyloidosis

Protein misfolding, organ tropism, morphology and clinicopathologic diagnosis

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish ATTRwt from autosomal-dominant ATTRv amyloidosis.

Trace TTR misfolding to extracellular amyloid accumulation and organ injury.

Explain cardiac and neuropathic phenotypes from deposit location.

Separate detection of amyloid from definitive identification of its protein.

A correct diagnosis requires both the amyloid phenotype and its molecular type.

Slide 3 · Amyloidosis is a protein-deposition disorder

Soluble protein

Misfolded conformer

Extracellular fibrils

Tissue dysfunction

Amyloid forms when aggregation-prone proteins accumulate as insoluble extracellular fibrils.

Clinical effects reflect progressive distortion and loss of normal tissue architecture.

Schematic

Slide 4 · Transthyretin has a normal transport role

Normal transthyretin (TTR)

A circulating plasma protein

Transports thyroxine and retinol-associated cargo

In ATTR disease

The same precursor becomes amyloidogenic

Fibrils accumulate in susceptible tissues

Slide 5 · Amyloid identity depends on the fibril protein

Amyloid type

Precursor protein

Source-supported context

AL

Immunoglobulin light chains

Clonal plasma-cell proliferation

ATTR

Transthyretin

Aging-associated or inherited

AA

Serum amyloid A–derived

Chronic inflammatory states

Slide 6 · Amyloid has a shared ultrastructural architecture

Continuous, nonbranching fibrils (schematic)

Nonbranching amyloid fibrils measure approximately 8–10 nm in diameter.

A cross-β-pleated organization produces a common staining signature across amyloid types.

Identical architecture does not imply identical precursor proteins.

Slide 7 · TTR aggregation follows a multistep process

TTR misfolding

Oligomer assembly

Fibril formation

Extracellular deposits

Aging of wild-type TTR or a TTR variant can initiate pathological misfolding.

Aggregates ultimately form insoluble amyloid fibrils in tissue.

Schematic

Slide 8 · Protein quality control normally limits aggregation

Misfolded protein

Degradation / clearance

Failure of clearance

Amyloid accumulation

Intracellular proteasomes and extracellular macrophages can remove misfolded proteins.

Amyloidogenesis reflects escape from these protective mechanisms.

Schematic

Slide 9 · Two routes generate aggregation-prone precursors

Amyloidogenic protein

Normal protein prone to aggregation

Variant protein prone to misfolding

Amyloid can arise from a normal protein that misfolds with aging or altered turnover.

Alternatively, an inherited altered protein may have heightened aggregation propensity.

Schematic

Slide 10 · ATTR is defined by its deposited protein

ATTR names amyloid fibrils derived from transthyretin.

TTR may be wild-type or genetically variant.

ATTR classification refers to protein origin—not just the affected organ.

Cardiac amyloidosis is a phenotype; ATTR specifies an amyloid type.

Deposit type and clinical phenotype answer different diagnostic questions.

Slide 11 · Amyloid can be localized or systemic

Localized deposits

Fibrils accumulate near their site of production

Distribution depends on the precursor

Systemic deposits

Circulating precursor can deposit in distant organs

ATTR commonly involves several susceptible tissues

Slide 12 · ATTR separates into two etiologic categories

TTR-derived amyloid

ATTRwt: Wild-type TTR

ATTRv: Inherited variant TTR

ATTRwt reflects aggregation of otherwise normal transthyretin.

ATTRv arises from a variant TTR polypeptide and is autosomal dominant.

Schematic

Slide 13 · ATTRwt develops without a TTR sequence variant

Wild-type TTR

Age-associated misfolding

Fibril deposition

Organ dysfunction

ATTRwt is an acquired, age-associated form of TTR amyloidosis.

Normal TTR can become insoluble and accumulate despite unchanged protein sequence.

Schematic

Slide 14 · ATTRwt primarily affects older adults

Typical presentation in men older than 70 years.

The heart is the principal involved organ.

ATTRwt is described as the second most common form of systemic amyloidosis.

Increasing prevalence is linked in the text to population aging.

Demographics are a clue, not a definitive biochemical amyloid type.

Slide 15 · The heart is the dominant ATTRwt target

Heart

Predominant deposition

Ligaments

Connective-tissue deposits possible

Other tissues

Site-dependent distribution

Wild-type TTR deposits commonly accumulate in myocardium.

Connective tissues, including ligaments, can also contain deposits.

Slide 16 · Ligament deposits broaden the ATTRwt phenotype

Cardiac disease

Amyloid in myocardium and associated structures

May produce restrictive physiology

Extracardiac involvement

TTR deposits in connective tissue

Organ distribution is not exclusively myocardial

Slide 17 · ATTRv reflects a genetically altered precursor

Inherited TTR variant

Variant protein folding

Amyloid fibrils

Target-organ deposits

TTR sequence variation can increase the tendency of the protein to misfold.

Variant-specific properties help determine tissue deposition patterns.

Schematic

Slide 18 · ATTRv follows autosomal-dominant inheritance

Familial TTR variant

Inheritance through a family line

Clinical expression can vary

The source identifies ATTRv as autosomal dominant.

Clinical severity cannot be predicted solely from carriage of a variant.

Schematic

Slide 19 · Different TTR variants favor different organs

Peripheral nerves

Polyneuropathy phenotype

Autonomic nerves

Autonomic neuropathy phenotype

Heart

Cardiomyopathy phenotype

Variant TTR polypeptides are associated with distinct organ tropism.

Both neurologic and cardiac patterns occur in hereditary families.

Slide 20 · Hereditary polyneuropathy is an ATTRv pattern

Variant TTR

Peripheral nerve deposits

Neural dysfunction

Polyneuropathy phenotype

Some hereditary ATTR families principally develop peripheral nerve amyloidosis.

The source calls this phenotype familial amyloid polyneuropathy.

Schematic

Slide 21 · Autonomic nerves can be involved in ATTRv

Variant TTR

Autonomic nerve deposits

Autonomic dysfunction

Clinical autonomic syndrome

Autonomic nerve involvement accompanies the neuropathic disease spectrum.

The anatomical location of deposits explains why manifestations differ across tissues.

Schematic

Slide 22 · Hereditary cardiomyopathy is another ATTRv pattern

Variant TTR

Cardiac amyloid

Reduced compliance

Familial cardiomyopathy

In other hereditary families, deposits predominantly accumulate in the heart.

The designation ATTRv-CM for familial transthyretin cardiomyopathy.

Schematic

Slide 23 · Clinical expression shows incomplete penetrance

Genetic status

The same pathogenic variant may be present in relatives

Autosomal-dominant inheritance

Observed disease

Severity differs substantially between carriers

Some develop severe disease; Others remain without disease

Slide 24 · Robbins gives a founder-variant example

The chapter describes a cardiac-amyloid-associated TTR variant linked to West African ancestry.

It reports carriage in approximately 4% of the African-American U.S. Population.

Cardiomyopathy has been recognized in heterozygotes and homozygotes.

Clinical penetrance is variable; Ancestry alone does not establish disease.

The quoted population estimate belongs to this textbook edition—not an individualized risk model.

Slide 25 · A TTR variant is not a clinical destiny

Variant TTR carrier

Clinically significant amyloidosis

No clinical disease recognized

The source describes marked variability among carriers.

Presence of an allele and evidence of tissue injury are distinct observations.

Schematic

Slide 26 · Wild-type and variant ATTR: Essential contrasts

Feature

ATTRwt

ATTRv

Precursor

Wild-type TTR

Variant TTR

Basis

Acquired / age-associated

Autosomal dominant

Characteristic organs

Heart; ligaments possible

Heart; peripheral/autonomic nerves

Phenotypic variability

Cardiac-predominant

Variant-specific tropism and penetrance

Slide 27 · Organ phenotype does not establish amyloid type

Cardiac deposition can arise from more than one amyloid precursor.

Similar extracellular material is seen with AL, ATTR and AA fibrils.

Typing the protein is necessary for a subtype-specific diagnosis.

A cardiac phenotype supports suspicion; Amyloid protein identification establishes type.

Slide 28 · Extracellular deposition distorts tissue architecture

Extracellular deposits expand between cells

Schematic—not a histologic specimen

Amyloid first accumulates between cells, often near basement membranes.

Increasing extracellular material compresses, isolates and may destroy adjacent parenchymal cells.

Slide 29 · Amyloid is eosinophilic and hyaline on H&E

Amorphous extracellular material

Schematic—not a histologic specimen

On H&E, deposits appear amorphous, eosinophilic and extracellular.

This appearance is not unique to TTR and can resemble other hyaline substances.

Slide 30 · Congo red highlights the amyloid deposit

Pink/red Congo red–positive tissue material

Congo red stains amyloid pink to red under ordinary transmitted light.

Staining identifies the material as amyloid but cannot specify ATTR by itself.

Slide 31 · Polarization reveals characteristic birefringence

Optical birefringence after Congo red + polarization

Congo red–stained amyloid shows characteristic apple-green birefringence under polarized light.

Its optical properties reflect the shared β-pleated fibril arrangement.

Slide 32 · Electron microscopy demonstrates fibrils

Continuous, nonbranching fibrils (schematic)

Amyloid consists of continuous, nonbranching fibrils.

Fibril diameter is about 8–10 nm.

Ultrastructure demonstrates amyloid architecture—not its unique molecular precursor.

Slide 33 · All amyloid types share a morphologic endpoint

Finding

What it supports

What it cannot resolve

Extracellular hyaline

Abnormal deposited material

Which precursor protein

Congo red birefringence

Amyloid fibrils

ATTR versus AL/AA

Nonbranching fibrils

Amyloid ultrastructure

Wild-type versus variant TTR

Slide 34 · Histologic confirmation and protein typing are distinct

Suspicious tissue

Confirm amyloid

Identify fibril type

Interpret organ disease

Morphologic techniques establish the presence of amyloid.

Biochemical typing is a second, indispensable classification step.

Schematic

Slide 35 · Immunohistochemistry can help distinguish types

Tissue finding

Confirmed Congo red–positive amyloid

Protein still unidentified

Type-specific assessment

Immunostains can distinguish TTR, AL and AA amyloid

Interpretation requires appropriate controls

Slide 36 · Mass spectrometry provides amyloid protein identity

Biopsy deposit

Proteomic analysis

Amyloid fibril protein

Subtype classification

Mass spectroscopy can identify amyloid types in specialized centers.

Protein-level identification separates the appearance of amyloid from its biochemical source.

Schematic

Slide 37 · Distribution alone is an unreliable amyloid classifier

Clinical distribution

Suggests organs at risk and directs sampling

May raise suspicion of ATTR

Biochemical identity

Requires investigation of fibril protein

Cannot be inferred from the organ map alone

Slide 38 · Cardiac amyloidosis may have subtle gross findings

The heart may appear near normal, firm or rubbery on gross inspection.

Chambers are usually normal in size but can become dilated.

Walls may be thickened as amyloid accumulates.

Absence of dramatic gross change does not exclude myocardial deposits.

Microscopy is often more decisive than gross appearance.

Slide 39 · Atrial endocardium may show waxy nodules

Reported gross feature

Small semitranslucent nodules

Resemble drops of wax

Anatomic site

Atrial endocardial surface

Especially left atrium in the description

Slide 40 · Amyloid occupies the cardiac interstitium

Interstitium with amyloid between myocytes

Schematic—not a histologic specimen

Hyaline eosinophilic material appears between cardiomyocytes.

Progressive interstitial deposits separate muscle fibers and compromise myocardial architecture.

Slide 41 · Cardiac deposits are not confined to myocardium

Interstitium

Myocyte separation

Conduction tissue

Electrical dysfunction

Small arteries

Luminal narrowing

Additional deposits may involve valves, endocardium and pericardium.

The dominant site explains diverse cardiac manifestations.

Slide 42 · Extracellular infiltration reduces compliance

Amyloid between myocytes

Stiff ventricular wall

Impaired filling

Restrictive physiology

A growing extracellular burden limits ventricular distensibility.

Restrictive cardiomyopathy is a common functional expression of cardiac amyloidosis.

Schematic

Slide 43 · Accumulating amyloid causes myocyte atrophy

Extracellular deposits expand between cells

Schematic—not a histologic specimen

Deposits progressively expand between cardiomyocytes.

Mechanical encroachment and pressure atrophy contribute to loss of viable muscle.

Slide 44 · Conduction-system involvement can be dangerous

Amyloid in conduction tissue

Electrical propagation disrupted

Conduction disturbance

Arrhythmia / risk of death

Subendocardial and conduction-system deposits can injure cardiac conduction pathways.

Conduction abnormalities and arrhythmias as serious cardiac consequences.

Schematic

Slide 45 · Intramural arterial deposits can cause ischemia

Less narrowed vessel lumen

Amyloid-laden vessel wall

Schematic—not histology

Amyloid may accumulate in the walls of small intramural coronary arteries.

Progressive vessel narrowing can impair myocardial perfusion even without large-vessel coronary disease.

Slide 46 · Cardiac presentation is clinically heterogeneous

Deposit location / burden

Possible expression

Extensive ventricular interstitium

Restrictive cardiomyopathy or heart failure

Conduction system

Rhythm or conduction abnormalities

Small intramural arteries

Small-vessel ischemia

Variable extent / location

Asymptomatic or disease mimicking other cardiac disorders

Slide 47 · Why a thick heart can still fill poorly

Morphologic observation

Ventricular walls may be thickened

Chamber size may remain normal

Physiologic consequence

Excess interstitial material stiffens myocardium

Filling restriction may dominate function

Slide 48 · Peripheral nerve involvement defines another axis

Variant TTR deposits

Peripheral neural structures

Structural compromise

Polyneuropathy phenotype

Hereditary ATTR may preferentially involve peripheral nerves instead of the heart.

The major phenotype is determined by tissue distribution, not by a different stain reaction.

Schematic

Slide 49 · Autonomic and somatic nerve disease can coexist

Peripheral nerves

Familial amyloid polyneuropathy

Peripheral nerve deposits

Autonomic nerves

Autonomic nerve involvement

Visceral regulation may be affected

Slide 50 · Connective-tissue deposits require context

Wild-type transthyretin deposits may be present in ligaments.

Finding amyloid outside myocardium is compatible with ATTRwt.

A particular ligament location alone does not identify the amyloid fibril protein.

Anatomical clues should lead to typing, not replace it.

Slide 51 · Variant-specific tropism and penetrance are different

Concept

Question answered

Source finding

Organ tropism

Where does amyloid tend to deposit?

Variant-specific cardiac or neural patterns

Penetrance

Will a carrier manifest disease?

Wide variability, including no disease

Disease severity

How severe is the phenotype?

May differ substantially among carriers

Slide 52 · Diagnostic reasoning begins with the tissue finding

Clinical organ dysfunction

Biopsy / tissue evaluation

Amyloid demonstrated

Amyloid typed

The source emphasizes histologic demonstration in appropriate tissue.

Typing resolves whether deposits are ATTR, AL or another amyloid.

Schematic

Slide 53 · Congo red positivity is not an ATTR diagnosis

Confirmed amyloid deposition

TTR-derived ATTR

AL / AA / other fibrils

Shared staining properties establish amyloid, not its protein of origin.

The precursor must be identified before a specific amyloidosis label is assigned.

Schematic

Slide 54 · ATTR and AL differ in precursor biology

Property

ATTR amyloidosis

AL amyloidosis

Fibril precursor

Transthyretin

Immunoglobulin light chains

Underlying biology

Age-related or inherited TTR misfolding

Clonal plasma-cell light-chain production

Overlap

Both may involve heart

Both may involve heart

Typing requirement

Demonstrate TTR origin

Demonstrate light-chain origin

Slide 55 · ATTR and AA differ in causal setting

Property

ATTR amyloidosis

AA amyloidosis

Precursor

Transthyretin

Serum amyloid A–derived

Major trigger

Wild-type aging / TTR variants

Persistent inflammatory stimulation

Common patterns

Cardiac; neural in ATTRv

Systemic, commonly renal in general AA

Shared feature

Extracellular amyloid fibrils

Extracellular amyloid fibrils

Slide 56 · Case: Older patient with a stiff ventricle

Hypothetical case: A man in his late 70s develops a restrictive cardiac phenotype. Tissue examination shows Congo red–positive deposits.

Which subtype is suggested, and what evidence is still missing?

ATTRwt is plausible from the age and phenotype, but Congo red does not establish TTR origin; Amyloid typing remains necessary.

Slide 57 · Case: Familial neuropathy with cardiac risk

Hypothetical case: A family has several members with progressive peripheral and autonomic neuropathy; Another relative has cardiomyopathy.

Which amyloidosis pattern best explains this family?

An autosomal-dominant ATTRv phenotype is consistent with variable TTR organ tropism and clinical expression. Confirm the deposited protein.

Slide 58 · Case: A positive stain without a protein type

Hypothetical case: A myocardial biopsy shows extracellular eosinophilic material with Congo red birefringence.

What has the pathologist actually proved?

Amyloid is present. The stain cannot prove ATTR; Type-specific immunohistochemistry or mass spectrometry can establish fibril identity.

Slide 59 · Common errors in interpreting ATTR

Potential error

Correct interpretation

“Congo red positive = ATTR”

Congo red confirms amyloid, not its type

“Any thick wall = ATTR”

Cardiac morphology needs amyloid evidence and typing

“Genotype predicts severity precisely”

Penetrance can vary substantially

“ATTRwt is strictly myocardial”

Ligament and other tissue deposition can occur

Slide 60 · Integrating precursor, tissue and phenotype

Wild-type / variant TTR

Fibril deposition

Organ-specific distortion

Clinical phenotype

The protein determines the molecular class; Its tissue distribution determines manifestations.

Amyloid morphology is shared, making subtype identification essential.

Schematic

Slide 61 · Consolidated diagnostic interpretation

ATTRwt: Age-associated wild-type TTR amyloid, usually cardiac-predominant.

ATTRv: Autosomal-dominant variant TTR, with variant-specific cardiac or neurologic involvement.

Congo red and ultrastructure establish amyloid; Protein identification establishes ATTR.

Cardiac dysfunction follows deposition within interstitium, vessels and conduction structures.

Interpret ATTR by integrating molecular precursor, tissue localization and functional injury.

Slide 62 · Primary textbook and internal source scope

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 6: Diseases of the Immune System, pp. 230–234.

Robbins, Cotran & Kumar. Pathologic Basis of Disease. 11th ed. Chapter 12: The Heart, pp. 522–523.

Primary topic: ATTR (Transthyretin) Amyloidosis; adjacent amyloid protein, morphology and clinical sections used for context.