Amyloidosis

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Amyloidosis

Amyloidosis describes a heterogeneous group of disorders characterized by extracellular deposition of misfolded proteins as insoluble fibrils that disrupt tissue architecture and cause organ dysfunction. More than 30 different precursor proteins can form amyloid in humans; 13 can cause systemic disease.

Structural Biology

All amyloid deposits share a remarkably uniform morphology regardless of their precursor protein:

Rigid, non-branching fibrils assembled on cross-beta scaffolds, reinforced by steric zipper motifs forming a stable beta-pleated sheet configuration
Associated non-fibrillar components: serum amyloid P (SAP), apolipoprotein E, glycosaminoglycans (heparan and dermatan sulfate groups), laminin, and collagen IV
On H&E stain: homogeneous, hyaline-like, eosinophilic extracellular material
On Congo red stain: pink/red in normal light; apple-green birefringence under polarized light - the gold standard diagnostic finding

Amyloid deposits stained with Congo Red showing apple-green birefringence under cross-polarized light

Congo Red staining of amyloid deposits showing characteristic apple-green birefringence - Firestein & Kelley's Textbook of Rheumatology

Other staining characteristics: weakly PAS-positive, diastase resistant, purple with crystal violet, positive with thioflavin T.

Pathogenesis

Organ dysfunction arises primarily from the abnormal tissue architecture created by deposits. Some amyloidogenic proteins additionally activate signaling pathways that produce ROS and impair calcium homeostasis.

Normally, misfolded proteins are degraded intracellularly by proteasomes or extracellularly by macrophages. In amyloidosis, these quality-control mechanisms fail. Amyloidogenic proteins fall into two broad categories:

Normal proteins produced in excess quantities that have an inherent tendency to misfold
Variant (mutant) proteins that are intrinsically prone to misfolding even at normal concentrations

Pathogenesis of amyloidosis - formation of AL, ATTRwt, AA, and ATTRv proteins

Pathogenesis diagram showing four major amyloidosis types - Robbins & Kumar Pathologic Basis of Disease

Classification

Type	Fibril Protein	Precursor	Associated Condition
AL (primary)	Immunoglobulin light chain (chiefly lambda)	Monoclonal plasma cell proliferation	Multiple myeloma, MGUS
AA (secondary)	Serum amyloid A (SAA)	Chronic inflammation - macrophages secrete IL-1/IL-6, driving hepatic SAA	Rheumatoid arthritis, Crohn's, FMF, TB
ATTRwt	Wild-type transthyretin	Liver; age-related destabilization	Elderly males (>70 yrs)
ATTRv	Variant transthyretin	Liver; >130 mutations, chromosome 18	Familial amyloid polyneuropathy/cardiomyopathy
Abeta	Beta-amyloid from APP cleavage	Neuronal/vascular	Alzheimer disease
Abeta2m	beta-2-microglobulin (MHC class I component)	Retained in renal failure	Long-term hemodialysis
ACal	Calcitonin precursor	C cells	Medullary thyroid carcinoma
AIAPP	Islet amyloid polypeptide	Pancreatic beta cells	Type 2 diabetes
AA	SAA	Autoinflammatory/IL-1 excess	Familial Mediterranean fever

Major Clinical Types in Detail

AL Amyloidosis (most common systemic form - ~2,000-3,000 new US cases/year)

Caused by clonal plasma cells synthesizing amyloidogenic immunoglobulin light chains (lambda > kappa)
Occurs in 5-15% of multiple myeloma patients; also with MGUS
Organ targets: heart (50-75%), kidneys (nephrotic syndrome), peripheral nerves, GI tract, liver, tongue (macroglossia), skin, respiratory tract
Untreated median survival of AL cardiomyopathy: 1.5 years

AA Amyloidosis (secondary)

Complicates chronic inflammatory/infectious diseases: RA, Crohn's, bronchiectasis, tuberculosis, osteomyelitis, FMF
Mechanism: chronic inflammation → macrophage activation → IL-1/IL-6 → hepatic SAA overproduction
Primary target: kidneys (proteinuria, nephrotic syndrome, eventually ESRD)
Treated by controlling the underlying inflammatory disease; colchicine effective in FMF-related AA
Potassium permanganate pretreatment abolishes Congo red staining of AA but not AL amyloid - useful for distinguishing the two histologically

ATTR Amyloidosis

Wild-type (ATTRwt): Age-related destabilization of the transthyretin tetramer (a liver-derived protein that carries <5% thyroxine and retinol-binding protein). Affects males >70 years primarily with restrictive cardiomyopathy. Untreated median survival: 3.6 years.

Variant (ATTRv): >130 mutations; most common in the US is Val122Ile (p.V142I) - present in 3.4% of Black Americans and common in those of African Caribbean descent. Causes cardiomyopathy and/or peripheral/autonomic neuropathy. Median survival untreated: 2.5 years.

Morphology / Organ Changes

Kidney: Deposits begin in mesangium and glomerular basement membrane → nephrotic syndrome → renal failure. Cortex appears enlarged and pale/waxy.

Heart: LV wall thickening, restrictive cardiomyopathy, HFpEF in early stages (HFrEF late). Cardiac amyloidosis particularly involves AL and ATTR types.

Liver: Amyloid deposits in space of Disse → hepatomegaly with "waxy liver" appearance. Liver function usually preserved early.

Spleen: "Sago spleen" (deposits in follicles) or "lardaceous spleen" (diffuse). Splenomegaly.

Nervous system: Peripheral neuropathy (especially vATTR), autonomic neuropathy, carpal tunnel syndrome (often a sentinel symptom of ATTRwt).

Diagnosis

Histology remains the gold standard: Congo red staining with apple-green birefringence under polarized light.

Sensitivity depends on amyloid quantity, correct tissue processing, and observer experience
A negative result does not exclude amyloidosis (patchy distribution)
Biopsy sites (in order of preference/yield): abdominal fat pad aspiration (sensitivity varies - only 45% for vATTR, 15% for wtATTR), rectal biopsy, minor salivary gland, affected organ (renal/endomyocardial biopsy)
Subtyping is mandatory after amyloid detection: immunohistochemistry (IHC), immunofluorescence, or - most accurately - laser microdissection/mass spectrometry proteomics

Cardiac-specific workup:

Echocardiography: concentric LV wall thickening (≥1.2 cm), granular/scintillating myocardial texture, biatrial enlargement, diastolic dysfunction, relative apical sparing pattern on global longitudinal strain (GLS) - hallmark finding
Cardiac MRI: late gadolinium enhancement in a diffuse, subendocardial/transmural pattern; T1 mapping elevated; extracellular volume (ECV) increased
Tc-99m pyrophosphate (PYP) / DPD / HMDP scintigraphy: Grade 2-3 uptake is highly specific for ATTR cardiomyopathy (>99% specificity when M-protein excluded); allows non-invasive diagnosis of ATTR without biopsy
ECG: low voltage (especially in AL), pseudo-infarct pattern, conduction abnormalities

Serum/urine tests: Serum free light chains, SPEP/UPEP (for AL); genetic testing for TTR mutations (all ATTR patients); SAA levels (for AA monitoring).

Treatment

AL Amyloidosis

The target is eliminating the clonal plasma cell source of amyloidogenic light chains:

Approach	Regimen	Notes
Autologous stem cell transplant (ASCT)	Myeloablative conditioning	Eligible patients only; transplant mortality ~2.5% at expert centers; 10-yr survival 53% if complete response
Standard chemotherapy	CyBorD (cyclophosphamide + bortezomib + dexamethasone)	Hematologic response 60%, cardiac response 17%
Daratumumab-based	Daratumumab + CyBorD (ANDROMEDA trial)	Complete response 53.3% vs 18.1% with CyBorD alone; now preferred first-line for transplant-ineligible

ATTR Amyloidosis

Three mechanistic strategies:

TTR tetramer stabilization: Tafamidis - the only FDA-approved drug for ATTR cardiomyopathy in the US; binds TTR's thyroxine-binding sites to prevent tetramer dissociation. ATTR-ACT trial demonstrated reduced mortality and CV hospitalizations.
TTR silencing (RNA-based therapies):
- Patisiran (siRNA) - FDA-approved for vATTR polyneuropathy; shown to reduce cardiac troponin T and NTproBNP
- Inotersen (antisense oligonucleotide) - FDA-approved for vATTR polyneuropathy
- Vutrisiran (siRNA) - approved for vATTR polyneuropathy; HELIOS-B trial data emerging for cardiomyopathy
- Eplontersen - emerging data
Fibril disruption/clearance: Investigational agents (doxycycline/tauroursodeoxycholic acid combinations, anti-fibril antibodies)

AA Amyloidosis

Treat the underlying disease - suppress SAA production
Colchicine for FMF (prevents attacks and SAA rises)
Biologic therapy (IL-1 or IL-6 inhibitors) for refractory inflammatory disease
Renal transplantation for ESRD (14% risk of amyloid recurrence in the graft)

Supportive / Heart Failure Management

Loop diuretics for fluid overload
Avoid digoxin (binds amyloid fibrils, can cause toxicity), calcium channel blockers (negative inotropy, may worsen), and high-dose ACE inhibitors/ARBs in hypotension
ICD for secondary prevention in carefully selected patients with expected survival >1 year

Recent Evidence

A 2025 systematic review on ATTR amyloidosis epidemiology (PMID 39819351) highlights that ATTRwt is substantially underdiagnosed in heart failure populations, with prevalence estimates as high as 13-17% in HFpEF with LV hypertrophy. This is driving increasingly aggressive screening efforts.

Sources: Robbins, Cotran & Kumar Pathologic Basis of Disease; Fuster & Hurst's The Heart, 15th Edition; Firestein & Kelley's Textbook of Rheumatology; Andrews' Diseases of the Skin; Brenner & Rector's The Kidney

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