Amyloidosis

Definition and Pathogenesis

Amyloidosis is a group of protein-misfolding diseases in which a precursor protein undergoes a conformational change, triggering the formation of amyloid fibrils that deposit in tissues and damage organ function. Despite differences in precursor protein structure, all amyloid fibrils share:

An antiparallel beta-pleated sheet (cross-β) configuration on X-ray diffraction
Fibril diameter of 2-5 nm (8-12 nm on electron microscopy), straight, non-branching
Binding of Congo red with characteristic apple-green birefringence under polarized light
Binding of thioflavin T (fluorescent stain)
Presence of serum amyloid P component (SAP) - a 25-kDa glycoprotein in all amyloid deposits

Over 30 different proteins have been implicated, but all ultimately form the same insoluble beta-pleated sheet configuration. - Goldman-Cecil Medicine, p. 1985; Brenner and Rector's The Kidney, p. 1488

Classification

I. Systemic Amyloidosis

Type	Precursor Protein	Cause
AL (formerly "primary")	Immunoglobulin light chain (κ or λ)	Clonal plasma cell dyscrasia / monoclonal gammopathy
AA (formerly "secondary")	Serum amyloid A (SAA)	Chronic inflammatory diseases (RA, IBD, FMF, osteomyelitis, TB)
ATTR - hereditary	Mutated transthyretin (TTR)	Inherited mutations (V30M most common, ~30-45% of cases)
ATTRwt ("wild-type" or senile)	Normal TTR	Age-related, predominantly cardiac, men >70 years
Aβ₂M (dialysis-related)	Beta-2 microglobulin	Long-term hemodialysis
Hereditary others	Fibrinogen α-chain, ApoA-I/A-II, lysozyme, gelsolin, LECT2	Rare gene mutations

Epidemiology: AL amyloidosis incidence ~12 per million/year. In referral series: ~60% AL, ~30% ATTR, ~3% AA. Median age at diagnosis: 59-63 years; men:women = 2:1. - Goldman-Cecil Medicine, p. 1986; Brenner & Rector, p. 1489

II. Cutaneous Amyloidosis

Macular amyloidosis - gray-brown, rippled macules (upper back/extremities), keratinocyte-derived
Lichen amyloidosis - intensely pruritic hyperkeratotic papules (shins)
Nodular amyloidosis - rare, AL-type deposits, systemic disease develops in ~10%
Secondary (tumor-associated) - adjacent to skin tumors

III. Heredofamilial Amyloidosis

Includes familial polyneuropathy (TTR V30M), familial cardiac amyloidosis, familial Mediterranean fever with AA amyloidosis, and other rare mutations.

Histology and Staining

Congo red - apple-green birefringence under polarized light (gold standard)
PAS - weakly positive, diastase-resistant
Crystal violet / methyl violet - metachromatic purple
Thioflavin T - fluorescent (sensitive screening)
Cotton dyes (Dylon, Pagoda Red) - intense orange
AA-specific: loses Congo red birefringence after potassium permanganate treatment (distinguishes AA from AL)
Electron microscopy: straight, non-branching, non-anastomosing filaments 60-100 nm in diameter
Immunohistochemistry: specific antibodies against precursor proteins confirm type; SAP antibody stains all forms
Andrews' Diseases of the Skin, p. 56-94

Clinical Manifestations

AL Amyloidosis - Multi-system Involvement

Organ	Frequency	Key Features
Kidney	50-58%	Nephrotic-range proteinuria, nephrotic syndrome; median cholesterol 270 mg/dL; most common presenting feature
Heart	40%	Restrictive cardiomyopathy, heart failure, arrhythmia, low-voltage ECG; predominant in ATTR
Peripheral nerves	~25%	Painful sensorimotor neuropathy, carpal tunnel syndrome, autonomic neuropathy
Liver	Common	Hepatomegaly, elevated alkaline phosphatase
GI tract	Variable	Malabsorption, motility disorders, GI bleeding
Skin/Soft tissue	~15%	Macroglossia (pathognomonic, dental indentations), periorbital/pinch purpura (vascular fragility)
Autonomic	Common	Orthostatic hypotension

Key physical signs (specific but only ~15% sensitive): macroglossia with dental indentations, periorbital "raccoon eye" purpura, pinch purpura.

Multisystem involvement is typical: 25% have 1 organ system, 36% have 2 systems, 38% have ≥3 systems involved. - Brenner & Rector, p. 1489

ATTR Amyloidosis

Wild-type: predominantly cardiac (heart failure in elderly men), bilateral carpal tunnel syndrome
Hereditary: peripheral/autonomic neuropathy + cardiac involvement, depending on mutation

AA Amyloidosis

Preceded by years of chronic inflammation
Predominantly renal involvement (proteinuria, nephrotic syndrome, CKD)
Hepatosplenomegaly common

Diagnosis

Biopsy

Abdominal fat pad aspiration - least invasive, 60-80% sensitive for AL
Bone marrow biopsy - useful when plasma cell dyscrasia suspected
Rectal biopsy - ~80% sensitive for systemic amyloid
Organ biopsy (kidney, liver, heart) - highest sensitivity but more invasive

Diagnosis requires Congo red-positive biopsy + amyloid typing. Typing is confirmed by:

Immunohistochemistry (IHC) - first-line, but false negatives in 14-35% of AL
Laser capture microdissection + mass spectrometry (LMD-MS) - gold standard for typing, especially rare subtypes

Serum/Urine Tests

Serum protein electrophoresis (SPEP) + immunofixation
Urine protein electrophoresis (UPEP) + immunofixation
Serum free light chain (FLC) assay - ~90% of AL patients have a paraprotein in serum/urine by immunofixation
24-hour urine protein quantification
NT-proBNP, troponin (cardiac involvement staging)

Imaging

Echocardiogram: granular sparkling myocardium, diastolic dysfunction, thickened walls, small cavity
Cardiac MRI: late gadolinium enhancement (LGE) - global subendocardial pattern
Technetium bone scan (99mTc-PYP/DPD/HMDP): highly sensitive for ATTRwt/ATTRh cardiac amyloid (grade 2-3 = diagnostic without biopsy if no monoclonal protein)
SAP scintigraphy (123I-SAP): maps whole-body amyloid burden and monitors regression

A recent practice guideline on laboratory workup of amyloidosis (Miller et al., 2025) provides updated guidance on the diagnostic algorithm.

Treatment

AL Amyloidosis

Goal: eliminate the clonal plasma cell population to stop light chain production.

Bortezomib-based regimens (CyBorD = cyclophosphamide + bortezomib + dexamethasone) - current standard of care first-line
Daratumumab + CyBorD - emerging as highly effective; ANDROMEDA trial showed deep hematologic responses
Autologous stem cell transplantation (ASCT) - for eligible patients (normal cardiac function, <2 organs involved); median survival >5 years in responders
Melphalan + dexamethasone - for transplant-ineligible patients
Hematologic response rates ~70% with modern therapy; deep responses (CR/VGPR) associated with organ improvement

AA Amyloidosis

Treat the underlying inflammatory disease (anti-TNF agents for RA, colchicine for FMF, antibiotics for chronic infection)
Goal: suppress SAA to <10 mg/L
Eprodisate (blocks proteoglycan binding) - studied but limited benefit
Colchicine for FMF-related AA amyloidosis is the standard per EULAR/PReS 2025 recommendations

ATTR Amyloidosis

Tafamidis (TTR stabilizer) - approved for ATTR cardiomyopathy; significantly reduces mortality (ATTR-ACT trial)
Diflunisal - older TTR stabilizer, used for hereditary ATTR polyneuropathy
Inotersen (antisense oligonucleotide) and Patisiran (siRNA/RNAi) - silence TTR gene expression; approved for hereditary ATTR with polyneuropathy
Vutrisiran (upgraded siRNA) - newer, quarterly dosing
Liver transplantation - removes the source of variant TTR; effective for V30M polyneuropathy if done early

Prognosis

AL amyloidosis: historically poor (median survival ~12-18 months), but modern bortezomib-based therapy achieves median survival >5 years in responders
Cardiac involvement is the main driver of mortality in AL and ATTR; NT-proBNP and troponin are key staging biomarkers (Mayo staging system)
AA amyloidosis: depends on control of underlying disease; renal function may stabilize or improve with inflammation suppression
ATTRwt: slowly progressive; median survival 3-4 years after diagnosis of heart failure
Amyloid deposits can regress with successful treatment (demonstrated by SAP scintigraphy)

Recent Evidence (2024-2026)

A 2025 systematic review on ATTR amyloidosis epidemiology highlights that wild-type ATTR is significantly under-recognized
Laboratory workup guidelines (2025) provide updated diagnostic pathways including mass spectrometry-based typing
EULAR/PReS 2025 updated treatment recommendations for AA amyloidosis in FMF

Sources: Goldman-Cecil Medicine (pp. 1985-1988), Brenner & Rector's The Kidney (pp. 1488-1490), Andrews' Diseases of the Skin (pp. 56-94)

This is a shared conversation. Sign in to Orris to start your own chat.