Amyloidosis (Lecture 2)

Slide 1 · Cardiac amyloidosis

Myocardial protein deposition and restrictive dysfunction

Etiology · morphology · clinicopathologic interpretation

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Define cardiac amyloidosis and identify its relationship to restrictive cardiomyopathy.

Compare AL, wild-type ATTR, variant ATTR and inflammation-related AA amyloid.

Interpret myocardial distribution, H&E and Congo red findings.

Connect deposition sites to diastolic dysfunction, arrhythmias and ischemic features.

Slide 3 · Cardiac amyloidosis: Defining lesion

Insoluble amyloid fibrils accumulate extracellularly within cardiac tissues.

The deposited proteins adopt a cross-β-pleated sheet architecture.

Accumulating amyloid alters tissue architecture and impairs cardiac function.

The classic presentation is a restrictive cardiomyopathy.

Amyloid is a protein deposit, not an inflammatory cellular infiltrate.

Slide 4 · Why it is a restrictive cardiomyopathy

Extracellular myocardial deposits

Reduced ventricular compliance

Impaired diastolic filling

Congestive cardiac dysfunction

The principal initial functional abnormality is impaired relaxation/filling, not a primary valve lesion.

Slide 5 · Systemic and predominantly cardiac disease

Systemic amyloidosis

Circulating amyloidogenic precursor

Heart plus one or more extracardiac tissues may be involved

Predominantly cardiac disease

Often age-associated ATTRwt

Deposits may be concentrated in the heart, with possible connective-tissue deposits

Slide 6 · From native protein to amyloid fibril

Normally soluble precursor

Misfolded/amyloidogenic protein

Oligomers and aggregates

Insoluble extracellular fibrils

Misfolding and aggregation—not simple protein abundance alone—define amyloid formation.

Slide 7 · The cross-β structure explains staining

Aggregated fibrillar architecture

Ordered Congo red binding

Birefringence under polarized light

The classic polarized-light finding reflects the molecular organization of amyloid.

Slide 8 · Amyloid is not starch

The historical name reflects earlier staining similarities to amylose.

Amyloid is composed of abnormal protein fibrils and associated molecules.

Deposits additionally bind proteoglycans, glycosaminoglycans and serum amyloid P.

“Amyloid” describes a shared deposit phenotype, not a single protein.

Slide 9 · Why extracellular protein accumulates

Amyloidogenic precursor production

Failure of folding/degradation control

Extracellular deposition

Progressive organ involvement

Both high precursor supply and intrinsic amyloidogenic sequence/structure may contribute.

Slide 10 · Two broad routes to amyloid

Excess production of susceptible proteins

Monoclonal light chains or chronic inflammatory SAA

Amyloidogenic fragments accumulate

Variant or age-dependent instability

Mutant or wild-type transthyretin

Misfolding produces ATTR fibrils

Slide 11 · Why myocytes fail despite being viable

Interstitial fibrils expand

Myocardial fibers become separated

Pressure-related myocyte atrophy

Reduced efficient tissue function

The source attributes most organ dysfunction to architectural distortion; Additional toxicity may occur.

Slide 12 · Possible direct cellular effects

Architectural disruption as the dominant injury mechanism.

Some amyloidogenic proteins may perturb signaling, increase reactive oxygen species or impair calcium homeostasis.

These proposed cellular effects supplement—but do not replace—mechanical infiltration as an explanation.

Slide 13 · Principal cardiac anatomic sites

Anatomic site

Functional consequence

Interstitial myocardium

Impaired compliance and myocyte compression

Conduction tissue

Electrical abnormalities or arrhythmias

Small intramural coronary vessels

Luminal narrowing and ischemia

Valves/endocardium

Valvular or surface manifestations

Slide 14 · Cardiac amyloid: Biochemical taxonomy

Amyloid

Fibril precursor

Setting

AL

Immunoglobulin light chain

Plasma cell clone

ATTRwt

Wild-type transthyretin

Age-associated aggregation

ATTRv

Variant transthyretin

Inherited TTR variant

AA

Serum amyloid A–derived fibrils

Chronic inflammation

Slide 15 · AL amyloid begins with a plasma cell clone

Monoclonal plasma cell proliferation

Abnormal free light-chain production

Light-chain misfolding

AL deposits in tissues

Cardiac AL may occur with overt myeloma or a less conspicuous plasma-cell proliferation.

Slide 16 · Light-chain sequence determines propensity

Not every free immunoglobulin light chain forms amyloid.

The specific amino-acid sequence contributes to amyloidogenic potential.

Both κ and λ chains can form deposits; λ is more frequently represented in AL.

An isolated light-chain laboratory abnormality is not identical to tissue-proven AL amyloidosis.

Slide 17 · AL amyloidosis does not require overt myeloma

AL with multiple myeloma

Overt plasma-cell tumor may produce abnormal immunoglobulins and amyloidogenic light chains.

Amyloid is an additional pathologic consequence.

AL without overt myeloma

A smaller clonal plasma-cell population can produce amyloidogenic light chains.

Protein toxicity/deposition may dominate the clinical picture.

Slide 18 · Systemic AL: Clues beyond the heart

Renal proteinuria or nephrotic syndrome suggests glomerular amyloid.

Peripheral nerve or autonomic dysfunction can accompany systemic deposition.

Tongue enlargement and gastrointestinal symptoms may arise from extra-cardiac deposits.

These findings support systemic involvement; None alone establishes fibril type.

Slide 19 · Transthyretin is a circulating transport protein

Transthyretin is synthesized principally in the liver.

In plasma it transports thyroxine and retinol-binding protein.

Both ordinary wild-type and sequence-variant TTR can form extracellular amyloid fibrils.

Biochemical identity, not gross myocardial appearance, distinguishes ATTR from AL.

Slide 20 · Wild-type ATTR: Age-associated deposition

Wild-type transthyretin

Age-related propensity to misfold

Progressive ATTRwt aggregation

Predominant cardiac amyloid

Cardiac disease in older adults, especially men.

Slide 21 · ATTRwt is not necessarily heart-exclusive

ATTRwt commonly deposits in the aging heart.

Transthyretin amyloid may also be found in connective tissues, including ligaments.

A cardiac-dominant presentation does not require every other organ to be amyloid-free.

Distribution should be described precisely rather than labeled automatically “localized.”

Slide 22 · Variant ATTR: An inherited protein disorder

Pathogenic TTR genetic variant

Amyloidogenic variant TTR

Extracellular deposition

Cardiac and/or nerve phenotypes

ATTRv is autosomal dominant, with variable penetrance and organ involvement.

Slide 23 · TTR genotype and organ phenotype differ

Cardiac-predominant variant

Amyloid deposition mainly involves myocardium.

Familial ATTR cardiomyopathy may result.

Neuropathy-predominant variant

Deposits favor peripheral and autonomic nerves.

Amyloid polyneuropathy may predominate.

Slide 24 · One TTR variant, variable penetrance

A West African founder-associated TTR substitution: Val122Ile.

Individuals with the variant may develop cardiac amyloidosis, but expression varies markedly.

Both heterozygous and homozygous carriers may be affected.

Carrier status alone does not establish clinical cardiac involvement.

Variant nomenclature follows the supplied textbook; Genetic testing requires appropriate clinical interpretation.

Slide 25 · ATTRwt versus ATTRv

Feature

ATTRwt

ATTRv

Precursor

Wild-type TTR

Sequence-variant TTR

Origin

Age-associated

Hereditary, autosomal dominant

Principal tissues

Heart; Sometimes ligaments

Heart and/or peripheral nerves

Clinical pattern

Often late-onset cardiac

Variable phenotype and penetrance

Slide 26 · AA amyloid: Inflammatory precursor pathway

Persistent inflammatory stimulus

IL-1/IL-6 and acute-phase response

Increased liver-derived SAA

AA amyloid deposits

Chronic inflammation can generate systemic amyloid; Cardiac involvement is possible but not its distinctive distribution.

Slide 27 · AA differs from AL and ATTR

Type

Underlying process

Important pattern

AL

Light-chain-producing plasma cell clone

Heart, kidney and other organs

ATTR

Wild-type or variant TTR

Heart and/or peripheral nerves

AA

Sustained inflammatory SAA production

Often kidney, liver and spleen

Slide 28 · Not all amyloid proteins explain cardiac disease

Aβ deposition is characteristic of cerebral plaques and some cerebral vessels.

β₂-microglobulin amyloid is classically associated with long-term dialysis and periarticular tissues.

Atrial natriuretic factor can produce isolated atrial amyloid.

A tissue diagnosis requires characterization of the actual deposited protein.

Slide 29 · Macroscopic appearance may be subtle

A heart with amyloid deposits can look nearly normal grossly.

Consistency may vary from ordinary to firm and rubbery.

Chamber dimensions are often preserved, despite substantial functional impairment.

A normal-looking heart does not exclude clinically important deposition.

Slide 30 · Wall thickening does not always imply hypertrophy

Amyloid infiltration

Extracellular deposits expand the wall.

Increased apparent wall thickness can coexist with myocyte atrophy.

Myocyte hypertrophy

Cardiomyocytes themselves enlarge.

Wall thickening arises from increased myocyte mass.

Slide 31 · Cardiac chambers may be normal or dilated

Chambers are usually of normal size in the classic restrictive phenotype.

Myocardial walls can appear thickened.

Chamber dilation is nevertheless documented in some cases.

Avoid treating any single gross configuration as obligatory.

Slide 32 · Atrial endocardial wax-like nodules

Small semitranslucent nodules can appear along the atrial endocardial surface.

The left atrial surface is a particularly noted site.

The gross appearance is likened to drips of wax.

This finding can prompt targeted tissue sampling but is not alone diagnostic.

Slide 33 · Interstitial myocardial amyloid

Cardiomyocyte

Extracellular amyloid

Schematic — not a photomicrograph

Amorphous eosinophilic material occupies spaces between myocardial fibers.

Interstitial expansion reduces normal tissue organization.

Progressive deposits may compress adjacent cardiomyocytes.

Slide 34 · Deposition around myocytes

Cardiomyocyte

Extracellular amyloid

Schematic — not a photomicrograph

Amyloid is extracellular, not a cytoplasmic storage inclusion.

Perimyocyte deposits can form broad, nearly confluent interstitial bands.

Pressure atrophy offers a structural explanation for progressive dysfunction.

Slide 35 · Small-vessel cardiac amyloid

Residual lumen

Amyloid within vessel wall

Schematic — not a histologic specimen

Amyloid can deposit within walls of intramural coronary arteries and arterioles.

Wall expansion may narrow or occlude the vascular lumen.

Small-vessel ischemia can occur without a large epicardial plaque.

Slide 36 · Conduction-system deposits

Amyloid in subendocardium/conduction tissue

Disruption of specialized electrical pathways

Conduction disturbances

Potential arrhythmia or syncope

The site of amyloid deposition helps explain apparently disproportionate electrical symptoms.

Slide 37 · Valve, endocardial and pericardial deposits

Valves, endocardium and pericardium among possible cardiac sites.

Location determines whether the disease resembles valvular pathology or other cardiac conditions.

Valve involvement should be distinguished from a primary degenerative or inflammatory valve lesion.

Slide 38 · Histology on routine H&E

Cardiomyocyte

Extracellular amyloid

Schematic — not a photomicrograph

Amyloid appears as extracellular, amorphous, hyaline eosinophilic material.

Deposits may encircle myocytes or accumulate in vessel walls.

H&E suggests amyloid but does not identify its fibril composition.

Slide 39 · H&E cannot distinguish amyloid from all hyaline

Amyloid on H&E

Eosinophilic, extracellular and amorphous.

Requires a confirmatory stain.

Other hyaline materials

Collagen or fibrin may resemble amyloid.

Morphology alone risks misclassification.

Slide 40 · Congo red in ordinary light

Congo red binds amyloid deposits and gives them a pink-red to red-orange appearance.

Detection must be interpreted in an appropriate tissue and histologic context.

The stain confirms amyloid-like fibrils but not whether the precursor is AL, ATTR or AA.

Slide 41 · Congo red under polarization

Congo red–stained fibrils

Polarizing microscopy

Characteristic birefringence

Support for amyloid deposition

Classic apple-green birefringence. The actual color can depend on optical conditions.

Slide 42 · Sulfated Alcian blue is an alternative

The cardiac chapter cites sulfated Alcian blue as another histochemical aid.

Histochemical positivity can help distinguish amyloid deposits from other extracellular substances.

A special-stain result does not replace biochemical amyloid typing.

Slide 43 · Electron microscopy: Fibrillar confirmation

Nonoriented thin extracellular fibrils on electron microscopy.

Ultrastructure corroborates a fibrillary deposit rather than a homogeneous intracellular inclusion.

Electron microscopy is confirmatory, not a substitute for typing the precursor.

Slide 44 · Confirming deposit ≠ identifying protein

H&E suggests extracellular deposit

Congo red supports amyloid

IHC and/or proteomic typing

Assign AL, ATTR, AA or another type

Correct amyloid typing matters because the etiologic disease differs fundamentally among types.

Slide 45 · Immunohistochemistry for amyloid typing

The systemic amyloidosis chapter describes immunostaining for AA, AL and TTR.

A subtype result requires appropriate interpretation of staining performance and specificity.

The aim is to identify the constituent fibril protein, not merely to demonstrate a deposit.

Slide 46 · Mass spectrometry for biochemical typing

Mass spectrometry as an available approach to typing amyloid.

Proteomic identification provides the basis for classifying otherwise similar Congo red–positive deposits.

Histology and protein identity answer different but complementary diagnostic questions.

Slide 47 · Diagnostic reasoning from tissue to etiology

Locate and sample affected tissue

Establish extracellular amyloid

Determine deposited fibril protein

Investigate its underlying precursor source

Do not infer “AL” solely from detecting an M protein in a patient with cardiac amyloid.

Slide 48 · The clinical spectrum is wide

Cardiac amyloid can be an unsuspected microscopic or asymptomatic finding.

Other patients show progressive restrictive heart failure.

Arrhythmia, dilation, valvular features or an ischemic mimic can predominate.

Clinical variation follows the location and burden of deposits.

Slide 49 · Mechanics of a stiff infiltrated ventricle

Expanded interstitial compartment

Reduced myocardial compliance

Greater resistance to ventricular filling

Diastolic dysfunction

The restrictive physiology arises from deposition within myocardium—not from external pericardial restraint.

Slide 50 · Heart failure in cardiac amyloidosis

Cardiac amyloid may produce insidious congestive heart failure.

The classical restrictive pattern links reduced compliance to raised filling pressures.

Symptoms may overlap with other cardiac diseases and are not pathognomonic.

Morphology establishes mechanism; Clinical findings establish physiologic impact.

Slide 51 · Electrical complications can dominate

Conduction tissue is a documented site of deposition.

The clinical consequences can include rhythm disturbance and syncope.

That conduction abnormalities and arrhythmias may be fatal.

Risk relates to distribution, not simply total visible myocardial amyloid.

Slide 52 · An ischemic presentation without large-vessel disease

Residual lumen

Amyloid within vessel wall

Schematic — not a histologic specimen

Intramural vascular amyloid narrows small coronary lumens.

Microvascular obstruction limits local myocardial perfusion.

The resulting syndrome may mimic ischemic heart disease.

Slide 53 · How cardiac amyloid mimics valve disease

Valvular and endocardial amyloid deposition can alter the presenting cardiac phenotype.

Coexisting chamber changes and arrhythmias can complicate bedside interpretation.

A valve-like clinical presentation does not establish a primary valve etiology.

Slide 54 · Why the phenotype can appear dilated

Most cases are restrictive, but Robbins explicitly recognizes chamber dilation.

A dilated appearance does not rule out amyloid protein deposition.

The diagnosis therefore requires structural and tissue correlation, rather than naming by silhouette alone.

Slide 55 · Recognizing a silent amyloid burden

Amyloid deposition may precede clinically overt mechanical impairment.

An incidental biopsy/autopsy finding should be interpreted by type and distribution.

Incidental deposition and symptomatic cardiomyopathy are not interchangeable labels.

Slide 56 · Extracardiac clues orient a systemic workup

Anatomic site

Functional consequence

Kidney

Proteinuria or nephrotic syndrome

Peripheral/autonomic nerves

Sensory, motor or autonomic manifestations

Tongue and gut

Macroglossia, malabsorption or altered digestion

Skin and vessels

Fragility or bleeding manifestations

Slide 57 · Renal involvement changes the presentation

Amyloid frequently affects glomeruli in systemic forms.

Progressive deposits can distort and ultimately obliterate capillary tufts.

Proteinuria may be severe enough to cause nephrotic syndrome.

Renal involvement raises concern for systemic disease in a patient with cardiac signs.

Slide 58 · Neuropathy may suggest a variant ATTR phenotype

Some ATTRv proteins preferentially deposit in peripheral and autonomic nerves.

Other variants predominantly produce cardiac disease.

Combined cardiac and neurologic manifestations should broaden the anatomic assessment.

The phenotype alone does not prove a particular genetic variant.

Slide 59 · Systemic AL can be associated with bleeding

Deposits within vessels may increase vascular fragility.

The text describes acquired factor X binding/inactivation in some AL cases.

These systemic manifestations can coexist with cardiac involvement.

They are supportive clues, not substitutes for amyloid typing.

Slide 60 · Choosing a diagnostic tissue site

Demonstration of amyloid in a suitable biopsy specimen.

Kidney may be sampled when renal involvement is prominent.

Rectal or gingival samples and abdominal fat aspirates may detect systemic disease.

Endomyocardial biopsy can identify an etiology in selected cardiac presentations.

Slide 61 · A negative fat aspirate does not exclude amyloid

Congo red staining of aspirated abdominal fat is an option for systemic assessment.

High specificity but limited sensitivity.

A negative result must be integrated with the strength of clinical suspicion and organ findings.

Do not treat tissue sampling sites as interchangeable.

Slide 62 · Investigating a possible AL precursor

Tissue-proven amyloid

Serum/urine protein investigations

Assess monoclonal light-chain production

Correlate with plasma-cell findings

Serum and urine electrophoretic testing and marrow examination in suspected AL.

Slide 63 · Bone marrow findings in AL

Marrow aspirates often show monoclonal plasmacytosis in AL amyloidosis.

An overt myeloma phenotype may be absent.

An underlying clonal plasma-cell population explains production of amyloidogenic free light chains.

The presence of a clone and the amyloid fibril type should be considered together.

Slide 64 · Cardiac amyloid versus endomyocardial fibrosis

Amyloidosis

Extracellular protein fibrils expand the interstitium and other cardiac tissues.

Congo red positivity is characteristic.

Endomyocardial fibrosis

Fibrous thickening predominantly affects endocardial/subendocardial regions.

A fibrotic rather than amyloid deposit is the key lesion.

Slide 65 · Amyloid thickening versus hypertrophic cardiomyopathy

Cardiac amyloidosis

Extracellular protein deposition may thicken walls.

Amyloid around fibers is central.

Hypertrophic cardiomyopathy

Sarcomeric disease may show myocyte hypertrophy/disarray.

Myocyte architecture, not amyloid, defines the lesion.

Slide 66 · Cardiac amyloid versus constrictive pericarditis

Restrictive amyloid

The intrinsic ventricular myocardium is stiff from interstitial deposits.

Extracellular amyloid is within cardiac tissues.

Constrictive pericarditis

The pericardium mechanically limits cardiac filling.

The primary pathology is pericardial constriction.

Slide 67 · Histologic pitfalls: What H&E cannot tell you

Amorphous pink material is not automatically amyloid.

Congo red positivity establishes a deposit phenotype but not subtype.

A negative extracardiac screening sample does not prove the heart is uninvolved.

Coexisting monoclonal protein does not independently determine cardiac amyloid type.

Slide 68 · Case: A stiff heart in later life

An older adult develops insidious heart failure with apparently thick ventricular walls.

The heart shows firm myocardium and interstitial extracellular deposits.

Congo red examination supports amyloid deposition.

Which biochemical possibilities must remain open before typing?

Slide 69 · Case reasoning: Old age is not a fibril type

ATTRwt is a strong etiologic consideration in older patients.

AL amyloidosis and variant ATTR remain clinically important alternatives.

Amyloid type must be established rather than inferred from age or gross appearance.

The physiologic diagnosis and the biochemical diagnosis answer separate questions.

Slide 70 · Case: Disproportionate electrical symptoms

A patient has conduction abnormalities and episodic syncope.

Histology reveals amyloid close to subendocardial conduction tissue.

There is less prominent diffuse interstitial expansion.

Which deposition site best links pathology to the clinical phenotype?

Slide 71 · Case reasoning: Distribution predicts phenotype

Conduction-system involvement can explain major electrical symptoms.

Interstitial burden may explain restrictive physiology in a different presentation.

Vascular involvement can account for ischemic manifestations.

The anatomic distribution of deposits is a major pathologic explanatory variable.

Slide 72 · Six clinicopathologic principles

Domain

Teaching conclusion

Protein

Amyloid is extracellular fibrillar material

Precursor

AL, ATTRwt, ATTRv and AA have distinct origins

Distribution

Interstitial, vascular, valvular and electrical tissues

Function

Usually restrictive, sometimes alternate phenotypes

Detection

Congo red with polarizing microscopy

Typing

Separate from the initial deposit identification

Slide 73 · Reading and image provenance

Robbins, Cotran & Kumar: Pathologic Basis of Disease, 11th ed. (2026).

The Heart: cardiomyopathies / cardiac amyloidosis.

Diseases of the Immune System: amyloid chemistry, classification and general morphologic diagnosis.

Histology panels not reproduced: diagnostic morphology is shown only as editable conceptual schematics.