Other Types of Amyloidosis

Slide 1 · Other types of amyloidosis

Familial • dialysis-associated • localized • endocrine deposits

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

Distinguish the principal uncommon amyloid syndromes by precursor protein and setting.

Explain why familial Mediterranean fever produces AA—not variant-protein—amyloid.

Connect dialysis-associated β₂-microglobulin with musculoskeletal manifestations.

Interpret localized and endocrine deposits without assuming systemic amyloidosis.

Use morphology and protein typing to approach a suspected case.

Slide 3 · Amyloid names describe fibril composition

Amyloidogenic precursor

Misfolding and aggregation

Extracellular fibril deposits

Local tissue dysfunction

Morphologically similar deposits can contain different proteins.

Correct typing therefore changes etiologic interpretation.

Slide 4 · One structure, multiple clinical diseases

Shared tissue signature

Extracellular amorphous deposits

Cross-β fibrillar configuration

Congo red binding and birefringence

Disease-specific features

Different precursor molecules

Different mechanisms of excess or misfolding

Different organ distribution and clinical associations

Slide 5 · Systemic and localized are different axes

Systemic disease

Amyloid may deposit far from protein production.

Multiple organs may be involved.

Organ complications reflect deposit burden and sites.

Localized disease

Deposits may remain restricted to one tissue.

Nodules or microscopic deposits may occur.

Absence of systemic involvement is part of the definition.

Slide 6 · A practical map of the less common forms

FMF-associated

AA fibrils • inherited autoinflammation

Long-term dialysis

β₂-microglobulin • musculoskeletal

Localized nodules

Often AL in some lesions

Endocrine deposits

Calcitonin or islet amyloid peptide

Slide 7 · The clinical setting is a clue—not amyloid typing

Congo red identifies amyloid, not its molecular species.

Neither the affected organ nor the gross appearance reliably defines subtype.

Link the clinical history to tissue findings and then identify the fibril protein.

AA, AL and TTR may be distinguished with specific immunohistochemistry; Mass spectrometry can type amyloid.

Slide 8 · Heredofamilial amyloidosis is heterogeneous

Multiple rare familial amyloid syndromes.

The fibril protein and dominant organs differ between families.

Familial Mediterranean fever exemplifies hereditary inflammation with secondary AA deposition.

Variant transthyretin amyloidosis is a separate inherited fibril-protein disorder.

Slide 9 · Familial Mediterranean fever: Inheritance and phenotype

Underlying disorder

Autosomal recessive hereditary syndrome

Autoinflammatory rather than monoclonal plasma-cell disease

Associated with abnormal regulation of inflammatory responses

Clinical attacks

Recurrent fever

Inflammation of serosal surfaces

Potential progression to widespread AA amyloidosis

Slide 10 · FMF attacks predominantly involve serosal tissues

Peritoneum

Inflammatory attacks may involve the abdominal serosa

Pleura

Inflammatory attacks may involve pleural surfaces

Synovial membrane

Joint-associated synovial inflammation

Systemic acute-phase response

Repeated inflammation can sustain SAA production

Slide 11 · Pyrin links the inherited defect to innate inflammation

Inherited pyrin-related disorder

Inflammasome regulation disturbed

Excess IL-1-associated inflammation

Recurrent inflammatory attacks

Pyrin participates in a protein complex regulating inflammatory reactions.

The excerpt does not define a single mutation-specific molecular mechanism.

Slide 12 · Inflammatory activity supplies the AA precursor

Excess IL-1-associated inflammation

Hepatic acute-phase response

Higher serum amyloid A (SAA)

AA-containing amyloid fibrils

The deposited AA fibril protein is derived from SAA.

Amyloid is a downstream consequence of sustained inflammatory protein production.

Slide 13 · FMF: Inherited disease, non-mutant fibril protein

FMF-associated AA

Genetic defect affects inflammatory regulation.

Excess cytokine activity increases SAA.

Deposits contain AA protein.

Variant TTR amyloidosis

The variant protein is itself amyloidogenic.

TTR misfolds and forms deposits.

The deposited protein is ATTRv.

Slide 14 · FMF has a geographically clustered distribution

Armenian, Sephardic Jewish, and Arabic ancestral groups.

Population association supports clinical suspicion; It is not a diagnostic criterion.

A family history and characteristic recurrent attacks strengthen the clinicopathologic context.

Confirm amyloid and determine protein identity rather than inferring AA solely from ancestry.

Slide 15 · Widespread AA amyloid can complicate FMF

Kidneys

Proteinuria or progressive renal dysfunction

Blood vessels

Vascular wall deposits

Spleen

Follicular or red-pulp involvement

Respiratory tract / liver

Possible respiratory involvement; Liver described as rare

Slide 16 · Why the kidney matters in FMF

Systemic AA deposition

Glomerular mesangial deposits

Capillary-lumen distortion

Proteinuria and possible kidney failure

Organ manifestations depend on deposit distribution and extent.

The same renal mechanism also applies to other systemic amyloid types.

Slide 17 · Contrast the two familial pathways

Feature

Familial Mediterranean fever

ATTRv amyloidosis

Inheritance

Autosomal recessive

Autosomal dominant

Proximal mechanism

Inflammatory IL-1 / SAA response

Variant TTR prone to misfolding

Fibril protein

AA

Variant transthyretin

Recognized pattern

Potentially widespread

Nerve or cardiac phenotypes

Slide 18 · Case: Recurrent serositis and renal protein loss

Clinical vignette

A patient has repeated episodes of fever with abdominal and pleural serosal inflammation. Later, marked proteinuria develops.

Which biochemical form of amyloid is most consistent with the Robbins-described syndrome?

Reasoned answer: AA amyloid, formed from SAA during sustained autoinflammatory activity.

Slide 19 · Dialysis-associated amyloid has a distinct precursor

β₂-microglobulin in circulation

Impaired removal in kidney failure

Long-term accumulation

Amyloid deposition near joints and soft tissues

β₂-microglobulin is a component of MHC class I molecules.

This is not the AL, AA or transthyretin precursor.

Slide 20 · β₂-microglobulin belongs to MHC class I

Physiologic context

Component of MHC class I molecules

Also present as a normal plasma protein

Pathologic context

Can accumulate in kidney disease

Fibrils may form in long-term dialysis

Deposits target musculoskeletal and periarticular tissues

Slide 21 · Historical dialysis membranes limited clearance

Kidney failure

High circulating β₂-microglobulin

Poor clearance through earlier filters

Progressive tissue retention / deposition

The text links past dialysis membranes to retention of β₂-microglobulin.

Improved filters have substantially reduced this complication.

Slide 22 · The distribution is predominantly musculoskeletal

Joints

Periarticular amyloid can contribute to symptoms

Tendons

Soft-tissue deposition

Ligaments

Particularly the carpal ligament

Muscles

Deposits may involve muscle tissue

Slide 23 · Carpal tunnel syndrome: A mechanical sequence

Carpal ligament amyloid

Added tissue volume / encroachment

Median-nerve compression

Carpal tunnel symptoms

Schematic causal sequence of the association.

Clinical assessment still requires consideration of other causes of median neuropathy.

Slide 24 · The carpal ligament is a key site

Schematic — not a clinical or histologic specimen

Simplified carpal tunnel cross-section

Carpal ligament

Amyloid

Median nerve

Deposit in ligament and periarticular tissues

Median nerve passes through a constrained space

Nerve compression links anatomy to symptoms

Slide 25 · Dialysis amyloid may extend beyond the wrist

Joints, muscles, tendons and ligaments are listed deposit sites.

Musculoskeletal symptoms do not specify the fibril type without tissue typing.

A long history of dialysis changes the differential diagnosis.

Pattern recognition is most useful when combined with a compatible specimen.

Slide 26 · Improved dialysis filters changed the disease frequency

Earlier dialysis era

Less effective β₂-microglobulin clearance

Circulating precursor retention

Recognized musculoskeletal amyloid complications

More recent filters

Improved precursor removal

Substantial decline in the complication reported by Robbins

Past history remains relevant to affected patients

Slide 27 · Dialysis amyloid versus FMF-associated AA

Feature

Dialysis-associated

FMF-associated

Precursor

β₂-microglobulin

SAA → AA

Clinical setting

Long-term hemodialysis

Autoinflammatory fever / serositis

Typical emphasis

Joints, tendons, ligaments

Potentially widespread systemic deposits

Illustrative symptom

Carpal tunnel syndrome

Proteinuria with systemic amyloid

Slide 28 · Case: Chronic dialysis and hand symptoms

Clinical vignette

A patient on long-term hemodialysis develops wrist symptoms associated with median-nerve compression and periarticular deposits.

Which fibril precursor is most characteristic of this clinical setting?

Reasoned answer: β₂-microglobulin, associated with dialysis-related musculoskeletal amyloid.

Slide 29 · Localized amyloid is defined anatomically

Localized

One organ or tissue is involved.

A visible nodule or microscopic deposit may be present.

The process does not necessarily imply systemic amyloidosis.

Systemic

Multiple organs may harbor deposits.

Deposits may occur away from synthesis of the precursor.

Organ involvement is an important clinical staging question.

Slide 30 · Localized deposits have two scales of presentation

Grossly apparent

Nodular amyloid masses

Microscopic only

Incidental small tissue deposits

Both patterns

Extracellular amyloid deposits

Interpretation

Examine the organ, distribution and precursor

Slide 31 · Recognized sites of localized amyloid nodules

Lung / larynx

Respiratory tract

Skin / periocular region

Cutaneous and ocular-adjacent tissues

Urinary bladder

Urinary tract

Tongue

Oral soft tissue

Slide 32 · Localized masses may have a plasma-cell rim

Schematic — not a clinical or histologic specimen

Central deposit with peripheral cells

Amyloid nodule

Peripheral inflammatory cells

Amyloid forms a central extracellular nodule.

Lymphocytes and plasma cells may lie at its edge.

The cell infiltrate is an observation, not proof of systemic disease.

Slide 33 · A subset of localized deposits consists of AL

Local plasma-cell population

Immunoglobulin light chain

Local extracellular aggregation

AL-type localized amyloid mass

AL protein in at least some localized cases.

Do not assume every localized amyloid nodule is AL.

Slide 34 · The important distinction is extent, not appearance

Microscopic amyloid can resemble systemic amyloid even when confined to one site.

A nodular mass alone cannot establish localized versus generalized distribution.

Protein typing identifies the deposited species.

Clinical assessment addresses whether additional organs are involved.

Slide 35 · Respiratory amyloid may be focal or diffuse

Focal pattern

Nodular deposits can occur in the lung or larynx.

A single mass may draw clinical attention.

Diffuse pattern

Respiratory involvement down to small bronchioles.

A broader airway distribution changes the clinicopathologic picture.

Slide 36 · Tongue amyloid can create a mass effect

Extracellular tissue deposit

Tongue enlargement / reduced flexibility

Impaired speech and swallowing

Clinical detection of oral involvement

The text describes tumor-forming amyloid and macroglossia.

Mass-forming behavior does not by itself establish malignancy.

Slide 37 · Case: A laryngeal amyloid nodule

Clinical vignette

Biopsy of a localized laryngeal nodule reveals Congo red–positive extracellular deposits with peripheral lymphocytes and plasma cells.

What inference is justified before completing the clinical workup?

Reasoned answer: A localized amyloid deposit is possible; Its AL composition and systemic extent remain to be established.

Slide 38 · Endocrine amyloid is often microscopically localized

Certain endocrine tumors contain amyloid deposits.

Medullary thyroid carcinoma, pancreatic islet tumors and pheochromocytoma.

Amyloid also occurs within islets in type 2 diabetes mellitus.

The precursor differs by endocrine setting and should not be assumed to be AL.

Slide 39 · Medullary thyroid carcinoma: Hormone-derived fibrils

Calcitonin polypeptide

Amyloidogenic endocrine material

Extracellular stromal deposits

Useful pathologic feature of MTC

The classification table lists the fibril as ACal (calcitonin-derived).

The presence of amyloid is helpful—not a standalone full diagnostic criterion.

Slide 40 · Amyloid can aid recognition of medullary thyroid cancer

Microscopic observation

Extracellular amyloid in the tumor stroma

Congo red–compatible staining behavior

Diagnostic interpretation

Supports medullary thyroid carcinoma in an appropriate lesion

Correlate with cellular morphology and other diagnostic workup

Do not identify a tumor solely from amyloid

Slide 41 · Type 2 diabetes: Islet amyloid polypeptide

Islet amyloid polypeptide

Islet-localized aggregation

Microscopic islet deposits

Type 2 diabetes association

The textbook table uses AIAPP for this fibril protein.

Islet amyloid is an endocrine deposit, not a synonym for systemic amyloidosis.

Slide 42 · Two endocrine deposits, two protein identities

Setting

Deposited protein

Anatomic site

Medullary thyroid carcinoma

Calcitonin-derived ACal

Tumor stroma

Type 2 diabetes mellitus

Islet amyloid polypeptide (AIAPP)

Islets of Langerhans

Other endocrine tumors

Protein not defined in this excerpt

Tumor-associated deposits

Slide 43 · Additional localized categories in the source table

Alzheimer disease

Aβ from amyloid precursor protein

Isolated atrial amyloid

Atrial natriuretic factor (AANF)

Endocrine tumors

Hormone-related or other proteins

Localized AL nodules

Light chains in some lesions

Slide 44 · Cerebral amyloid is a distinct organ pattern

Alzheimer disease

Aβ deposition in cerebral plaques

Also in walls of cerebral blood vessels

Precursor: Amyloid precursor protein (APP)

Other amyloid types

Have different fibril precursors

May be localized or systemic

Cannot be typed by Congo red color alone

Slide 45 · Amyloid accumulates outside cells

Schematic — not a clinical or histologic specimen

Extracellular amyloid around cells

Deposits arise in extracellular interstitial spaces.

They often form adjacent to basement membranes.

Progressive accumulation displaces and damages cells.

Slide 46 · Why amyloid produces pressure atrophy

Extracellular fibril accumulation

Compression of neighboring cells

Tissue architectural distortion

Functional impairment

Tissue pressure and destruction.

Extensive inflammation is not required to explain damage.

Slide 47 · Grossly, extensive amyloid can be waxy and firm

Small deposits

May be invisible on gross examination

Require microscopic detection

Large deposits

Organ often becomes enlarged

Gray, waxy and firm cut surface

Distribution depends on involved tissue

Slide 48 · H&E morphology is suggestive, not specific

Typical appearance

Amorphous extracellular material

Eosinophilic or hyaline quality

Expansion of tissue compartments

Important limitation

Other hyaline materials may look similar

Collagen and fibrin enter the differential

A special stain establishes the characteristic reaction

Slide 49 · Congo red: Ordinary versus polarized light

Schematic — not a clinical or histologic specimen

Same deposit under different illumination

Ordinary light

Polarized light

Ordinary light: Pink-red amyloid deposits

Polarized light: Characteristic apple-green / yellow-green birefringence

The reaction reflects fibril cross-β organization

Slide 50 · Birefringence reflects molecular organization

Cross-β pleated fibril arrangement

Ordered Congo red dye binding

Characteristic polarized-light response

Morphologic confirmation of amyloid

The staining property is shared across chemically distinct amyloid types.

It does not identify AA versus AL versus ATTR.

Slide 51 · Electron microscopy shows thin nonbranching fibrils

Schematic — not a clinical or histologic specimen

Nonbranching extracellular fibrils

Schematic parallel fibrils

Approximately 8–10 nm fibrils are.

Fibers are nonbranching and extracellular.

Electron microscopy supports identity but does not supply protein type.

Slide 52 · Typing the protein is a separate diagnostic step

Biopsy confirms amyloid

Review clinical distribution

Specific immunohistochemistry

Mass spectrometric typing where available

Immunohistochemistry for AA, AL and TTR.

Its text reports mass spectrometry as capable of identifying amyloid types.

Slide 53 · Organ distribution suggests—but does not prove—type

AA in chronic inflammation

Kidney, liver, spleen and lymph nodes often affected

Adrenals and thyroid also described

AL with plasma-cell proliferation

Heart, GI tract and respiratory tract emphasized

Peripheral nerves, skin and tongue often involved

Overlap prevents diagnosis by anatomy alone

Slide 54 · Renal amyloid begins in mesangium and capillaries

Schematic — not a clinical or histologic specimen

Schematic glomerulus: Progression of deposition

Early

Advanced

Early mesangial matrix expansion

Uneven capillary basement-membrane thickening

Progressive lumen narrowing and obliteration

Slide 55 · Renal architecture explains proteinuria

Amyloid within glomerular tuft

Distorted filtration barrier

Proteinuria / nephrotic syndrome

Progressive renal insufficiency

This is a shared organ-effect mechanism rather than a feature unique to FMF.

Slide 56 · Splenic deposition has two named patterns

Sago spleen

Amyloid largely in splenic follicles

Small, tapioca-like gross granules

Lardaceous spleen

Amyloid in red-pulp sinus walls and framework

Coalescent map-like deposits

Different appearance, same amyloid principle

Slide 57 · Hepatic amyloid expands the space of Disse

Perisinusoidal deposition

Encroachment on hepatocytes

Pressure atrophy / loss

Hepatomegaly may occur

The source notes that liver function may remain preserved despite extensive deposits.

Slide 58 · Cardiac amyloid compromises muscle and conduction

Interstitial / subendocardial deposits

Myocyte pressure atrophy

Stiff myocardium and/or conduction injury

Failure, arrhythmia or restrictive physiology

Not all hearts show striking gross abnormalities.

Slide 59 · Vessel-wall deposition can cause bleeding

Structural injury

Amyloid infiltration can make vessels fragile.

Bleeding may follow minor trauma or occur spontaneously.

Specific AL-associated mechanism

In some cases AL amyloid binds factor X.

Factor X inactivation can aggravate bleeding.

Slide 60 · Amyloidosis may present nonspecifically

Early manifestations can include weakness or weight loss.

Lightheadedness and syncope may occur.

More informative findings arise from renal, cardiac, GI or nerve involvement.

A normal-appearing organ does not exclude microscopic amyloid.

Slide 61 · Biopsy establishes amyloid; Distribution frames the workup

Clinical organ clue

Appropriate tissue sample

Congo red and polarized exam

Fibril typing + extent assessment

Kidney may be sampled in renal presentations.

Other described sites include rectum, gingiva and abdominal fat aspirate.

Slide 62 · Abdominal fat aspiration has a limitation

Potential utility

Can support diagnosis of systemic amyloid

Minimally invasive compared with organ biopsy

Important limitation

Low sensitivity despite specificity

A negative sample does not automatically exclude disease

Interpret according to clinical suspicion

Slide 63 · A suspected AL pattern requires clonal evaluation

Serum and urine protein electrophoresis and immunoelectrophoresis are described.

Bone marrow may show a monoclonal plasma-cell population.

Systemic AL can exist even without overt multiple myeloma.

These tests assess the source of AL, not the histologic staining reaction.

Slide 64 · Diagnostic cases: Ask two distinct questions

Is amyloid present?

Extracellular deposit morphology

Congo red staining

Polarized-light birefringence

Which amyloid and where?

Protein typing: IHC or mass spectrometry

Clinical setting and organ distribution

Workup for the implicated precursor

Slide 65 · Case: Endocrine amyloid in thyroid tumor

Clinical vignette

Histology of a thyroid neoplasm shows extracellular amyloid material within the tumor.

Which source-derived peptide should enter the differential, and what is the appropriate interpretation?

Reasoned answer: Calcitonin-derived ACal; A helpful finding in medullary thyroid carcinoma, not sufficient by itself to establish diagnosis.

Slide 66 · Case: Amyloid in a single cutaneous nodule

Clinical vignette

A skin nodule contains Congo red–positive deposits with neighboring plasma cells. Examination has not established involvement elsewhere.

What should remain unresolved before labeling the disease?

Reasoned answer: Whether the deposit is localized or part of systemic amyloidosis, and whether the fibril is AL or another type.

Slide 67 · Case: The protein determines classification

Clinical clue

Candidate protein

Reason

Recurrent familial serositis

AA

IL-1 response drives SAA

Long-term hemodialysis / carpal tunnel

β₂-microglobulin

Reduced clearance / periarticular deposits

Medullary thyroid carcinoma

Calcitonin-derived ACal

Endocrine peptide source

Type 2 diabetes / islets

AIAPP

Islet amyloid polypeptide

Slide 68 · Integrating pattern, protein and consequence

Predisposition

Inherited inflammation, dialysis retention or local peptide production

Protein

AA, β₂-microglobulin, AL, ACal or AIAPP

Distribution

Systemic versus organ-limited

Damage

Compression, architectural distortion and organ dysfunction

Slide 69 · Core distinctions to retain

FMF: Hereditary autoinflammation with SAA-derived AA deposition.

Dialysis: β₂-microglobulin deposits in joint and soft tissues, especially around the wrist.

Localized nodules: Distribution can be restricted; Some are AL and plasma-cell associated.

Endocrine: Hormone / islet peptide-derived amyloid, including calcitonin in medullary thyroid carcinoma.

Congo red confirms amyloid, while protein typing establishes subtype.

Slide 70 · Primary source and study boundaries

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. (2026). Chapter 6, “Amyloidosis,” particularly “Other Types of Amyloidosis,” pp. 230–235.

The lecture also uses the adjacent primary-source sections on amyloid structure, classification, AL, ATTR and AA for essential context.

Diagrams are original editable conceptual schematics. No diagnostic photomicrographs are reproduced because source figure files were not provided.