Amyloidosis
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"amyloidosis"[MeSH Terms] AND treatment
Goldman-Cecil has a dedicated systemic amyloidosis section. Let me pull the main textbook content and the Andrews' dermatology classification in parallel.
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Good foundational content. Now let me pull pathology, diagnosis, and treatment sections from Goldman-Cecil, plus the Brenner kidney section.
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Excellent detail. Now let me get the treatment and diagnosis content from Goldman-Cecil (the ATTR and AL treatment sections), and also check the clinical manifestations more fully.
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The block seems to be referencing the myeloma section. Let me read the actual amyloidosis treatment block from the correct location, and also the Brenner kidney section for renal amyloidosis treatment.
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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)
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