While amyloidosis may seem like a rare disease, the statistics tell a more complex story: its many forms touch far more lives than you might think, impacting everyone from patients on long-term dialysis to otherwise healthy elderly individuals.
Key Takeaways
- The annual incidence of AL amyloidosis in the United States is approximately 12.8 cases per million person-years
- In Europe, the incidence of systemic AL amyloidosis is estimated at 8-12 cases per million population per year
- ATTR amyloidosis prevalence in individuals over 60 years old is about 1 in 300 in autopsy studies from Western populations
- AL amyloidosis is classified into immunoglobulin light chain (AL), accounting for ~70% of systemic cases
- Transthyretin (ATTR) amyloidosis is divided into wild-type (ATTRwt) and variant (ATTRv) subtypes, with ATTRwt being age-related
- AA amyloidosis is secondary to chronic inflammation, derived from serum amyloid A protein
- Most common symptom in AL amyloidosis is fatigue, present in 90% of patients at diagnosis
- Peripheral neuropathy affects 20-30% of AL amyloidosis patients, often painful small-fiber type
- Cardiac involvement in amyloidosis presents with heart failure symptoms in 50-60% of systemic cases
- Serum free light chain ratio abnormal in 95% of AL amyloidosis at diagnosis
- Congo red staining with apple-green birefringence under polarized light confirmatory for amyloid, sensitivity 100%
- Technetium-99m pyrophosphate (Tc-PYP) scan specificity >90% for ATTR cardiac amyloidosis
- Chemotherapy with bortezomib-based regimens achieves hematologic response in 60-70% newly diagnosed AL
- Daratumumab added to CyBorD increases CR rate to 53% vs 18% in AL amyloidosis
- Tafamidis stabilizes TTR, reduces mortality by 30% in ATTR cardiomyopathy (ATTR-ACT trial)
Amyloidosis, including its common types AL and ATTR, varies widely in incidence, diagnosis age, and survival.
Diagnosis
- Serum free light chain ratio abnormal in 95% of AL amyloidosis at diagnosis
- Congo red staining with apple-green birefringence under polarized light confirmatory for amyloid, sensitivity 100%
- Technetium-99m pyrophosphate (Tc-PYP) scan specificity >90% for ATTR cardiac amyloidosis
- Bone marrow biopsy shows plasma cells >10% in 60-70% of AL amyloidosis
- Mass spectrometry on laser microdissected tissue identifies amyloid protein type in 95% cases
- Echocardiography shows increased left ventricular wall thickness >12mm in 90% cardiac amyloid
- Serum cardiac troponin T elevated in 75% of AL cardiac amyloidosis
- NT-proBNP >1800 pg/mL highly suggestive of cardiac amyloid in low-flow low-gradient AS
- Genetic testing for TTR mutations positive in 100% hereditary ATTRv
- Urine/serum immunofixation detects M-protein in 90% AL amyloidosis
- Cardiac MRI late gadolinium enhancement in subendocardium specificity 90% for amyloid
- Kidney biopsy immunofluorescence shows light chain restriction in AL renal amyloid
- Scintigraphy with 99mTc-DPD similar to PYP, Grade 2-3 uptake diagnostic for ATTR
- Flow cytometry on bone marrow detects clonal plasma cells in 80% AL
- Abdominal fat pad aspirate sensitivity 70-80% for systemic amyloid detection
- Strain echocardiography global longitudinal strain <-15% with apical sparing pattern in 85%
- SAA protein levels >10mg/L indicate risk for AA amyloidosis in chronic inflammation
- Beta-2 microglobulin >28mg/L in dialysis patients suggests Aβ2M amyloidosis
- PET-CT with amyloid tracers like 18F-florbetapir emerging for non-invasive typing
- Mayo AL staging: troponin, NT-proBNP, dFLC stratifies risk with median survival 94 vs 12 months
- Rectal biopsy sensitivity 80% for systemic amyloidosis diagnosis
- Electrophysiology shows small-fiber neuropathy in skin biopsy for early ATTRv
- Liver biopsy for hepatomegaly shows amyloid in sinusoids
- Urine protein electrophoresis shows Bence Jones proteins in 70% AL
- ECG low voltage despite hypertrophy in 60% cardiac amyloidosis
- Complete hematologic response (CR) defined as dFLC <10mg/L and normal ratio in AL treatment
Diagnosis Interpretation
This collection of data makes amyloidosis diagnostics feel like assembling a sinister jigsaw puzzle, where each piece, from the eerie green glow of a Congo red stain to the cardiac MRI's specific pattern of scarring, fits together to reveal a precise and often ominous picture of protein infiltration.
Epidemiology
- The annual incidence of AL amyloidosis in the United States is approximately 12.8 cases per million person-years
- In Europe, the incidence of systemic AL amyloidosis is estimated at 8-12 cases per million population per year
- ATTR amyloidosis prevalence in individuals over 60 years old is about 1 in 300 in autopsy studies from Western populations
- AA amyloidosis accounts for 2-5% of all renal biopsies in developing countries due to chronic infections
- The median age at diagnosis for light chain (AL) amyloidosis is 63 years, with 60% of patients being male
- Hereditary amyloidosis due to TTR mutations has a prevalence of 1 in 100,000 worldwide but higher in specific endemic areas like Portugal
- Dialysis-related amyloidosis (Aβ2M) affects up to 20% of patients on long-term hemodialysis after 5 years
- Localized cutaneous amyloidosis incidence is around 0.1-0.5 cases per 100,000 person-years, predominantly in Asian populations
- In Olmsted County, Minnesota, the age- and sex-adjusted incidence of AL amyloidosis rose from 3.7 to 14.2 per million between 1983-2007
- Wild-type ATTR cardiac amyloidosis prevalence increases to 25% in patients over 80 years undergoing valve surgery
- AL amyloidosis represents 70-80% of all systemic amyloidosis cases diagnosed in referral centers
- In the UK, AA amyloidosis secondary to rheumatoid arthritis has declined to less than 1% of cases due to better RA treatment
- Global prevalence of familial Mediterranean fever-associated AA amyloidosis is highest in Sephardic Jews and Armenians at 1-2%
- Senile systemic amyloidosis (now wild-type ATTR) autopsy prevalence is 10-15% in hearts of individuals over 75
- AL amyloidosis incidence is twice as high in African Americans compared to Caucasians
- Cerebral amyloid angiopathy affects 20-40% of elderly brains at autopsy
- In Japan, ATTRv amyloidosis due to Val30Met mutation has an endemic prevalence of 0.1% in certain regions
- Long-term peritoneal dialysis patients have a 20% cumulative incidence of Aβ2M amyloidosis after 10 years
- AL amyloidosis is diagnosed in 15-20% of patients with multiple myeloma
- Prevalence of monoclonal gammopathy in AL amyloidosis patients is nearly 100%
- AA amyloidosis incidence has decreased by 80% in Europe over the last 30 years due to anti-inflammatory therapies
- Wild-type ATTR amyloidosis is found in 13% of patients with severe aortic stenosis referred for TAVR
- Hereditary transthyretin amyloidosis affects approximately 50,000 people worldwide
- In Sweden, the incidence of AL amyloidosis is 8.9 per million person-years
- Localized AL amyloidosis of the skin represents 5-10% of primary amyloidosis cases
- AA amyloidosis due to chronic infections like tuberculosis is prevalent in 10-20% of cases in low-income countries
- Cardiac involvement in wild-type ATTR amyloidosis is present in 90% of diagnosed cases
- The male-to-female ratio in wild-type ATTR cardiac amyloidosis is 20:1
- AL amyloidosis survival without treatment is median 12 months
- Prevalence of ATTR amyloidosis in heart failure with preserved ejection fraction patients over 65 is up to 15%
Epidemiology Interpretation
The world of amyloidosis is a statistically precise but geographically capricious one, whispering that while a rare disease is overall a rare disease, it becomes startlingly common the moment you look at the right—or perhaps the wrong—aging organ, genetic lineage, or dialysis chair.
Prognosis
- Median overall survival for AL amyloidosis with early autologous stem cell transplant is 94 months
- Stage III AL amyloidosis has median survival of 4-8 months regardless of treatment
- Wild-type ATTR-CM median survival 3.6 years from diagnosis
- ATTRv polyneuropathy median survival 7-12 years, shorter with cardiac involvement
- AA amyloidosis renal survival 50% at 10 years with ESRD prevention
- Untreated AL amyloidosis median survival 6-12 months
- Post-heart transplant AL survival 50% at 10 years if hematologic CR achieved
- Tafamidis-treated ATTR-CM all-cause mortality reduced 30% vs placebo at 30 months
- Patisiran improves survival hazard ratio 0.45 in ATTRv cardiomyopathy subgroup
- Complete hematologic response in AL predicts 5-year survival >60%
- Cardiac biomarker stage I AL: median survival >10 years
- Dialysis-related amyloidosis median survival 5-10 years post-dialysis initiation
- Liver involvement > Stage 3 in AL reduces median survival to 18 months
- Mayo 2012 cardiac staging for ATTR: stage 3 median 23 months
- Hereditary ATTR post-liver transplant survival 80% at 5 years if early
- ALECT2 amyloidosis renal prognosis better, median renal survival 80 months
- FMF AA amyloidosis with colchicine: end-stage renal disease incidence <5%
- Advanced cardiac amyloidosis NYHA IV median survival 4 months
- VGPR or better in AL with bortezomib median survival 6.1 years
- Wild-type ATTR lumbar stenosis worsens prognosis, median 2 years survival
- No cardiac involvement AL median survival doubles to 48 months
- Daratumumab trial: PFS not reached vs 47 months with VCd
Prognosis Interpretation
These statistics reveal a sobering truth: while effective treatments can dramatically extend the clock, the relentless progression of amyloidosis underscores that our race against it begins and is often won or lost with the very first diagnosis.
Symptoms
- Most common symptom in AL amyloidosis is fatigue, present in 90% of patients at diagnosis
- Peripheral neuropathy affects 20-30% of AL amyloidosis patients, often painful small-fiber type
- Cardiac involvement in amyloidosis presents with heart failure symptoms in 50-60% of systemic cases
- Macroglossia (enlarged tongue) is pathognomonic, occurring in 10-20% of AL amyloidosis
- Nephrotic syndrome due to renal amyloidosis in 50-70% of AA and AL cases
- Autonomic dysfunction like orthostatic hypotension in 15-30% of patients with cardiac amyloidosis
- Periorbital purpura ('raccoon eyes') classic in AL, seen after Valsalva in 15%
- Carpal tunnel syndrome precedes wild-type ATTR cardiac amyloidosis by 5-10 years in 50% of cases
- Lumbar spinal stenosis from Aβ2M deposition in 30-50% of long-term dialysis patients
- Weight loss and anorexia in 40% of advanced AL amyloidosis patients
- Hepatomegaly without enzyme elevation in 25-40% of AL with liver involvement
- Bilateral shoulder pad sign (muscle pseudohypertrophy) in ATTRv amyloidosis
- Corneal lattice dystrophy in gelsolin amyloidosis, affecting 90% of carriers
- Gastrointestinal bleeding or malabsorption in 10-20% of systemic amyloidosis
- Edema in 60% of renal amyloidosis patients due to proteinuria >3g/day
- Dyspnea on exertion primary symptom in cardiac amyloidosis, NYHA class II-III in 70%
- Syncope or pre-syncope from conduction disease in 30% of ATTR cardiac amyloidosis
- Skin lesions in localized amyloidosis: papules, plaques, or nodules in 80%
- Hoarseness from laryngeal amyloidosis in 5-10% of localized cases
- Bone pain from amyloidomas rare, <1% of cases
- Respiratory symptoms like dyspnea from pulmonary amyloid in 5%
- Facial nerve palsy in cranial neuropathy of ATTRv
- Arthralgias and joint destruction in Aβ2M amyloidosis
- Palpebral conjunctival involvement with subepithelial hemorrhage in AL
- Exercise intolerance measured by 6-minute walk test <300m in 50% advanced cardiac amyloid
Symptoms Interpretation
While these statistics reveal that amyloidosis can hijack nearly any organ in the body, the most glaring symptom is the sheer exhaustion it inflicts, with nine out of ten patients arriving at their diagnosis already consumed by profound fatigue.
Treatment
- Chemotherapy with bortezomib-based regimens achieves hematologic response in 60-70% newly diagnosed AL
- Daratumumab added to CyBorD increases CR rate to 53% vs 18% in AL amyloidosis
- Tafamidis stabilizes TTR, reduces mortality by 30% in ATTR cardiomyopathy (ATTR-ACT trial)
- Patisiran (siRNA) reduces TTR 80%, halts neuropathy progression in 60% ATTRv (APOLLO)
- Inotersen (ASO) lowers TTR 77%, improves mNIS+7 score in ATTRv (NEURO-TTR)
- Stem cell transplant post-melphalan achieves 40% CR in eligible AL patients
- Colchicine prevents AA amyloidosis progression in FMF, 90% effective
- Dialysis modality switch to peritoneal reduces Aβ2M symptoms in 50%
- Heart transplant survival 60% at 5 years in AL post-chemo remission
- Diflunisal stabilizes TTR tetramers, slows progression in ATTRv by 50% (pre-clinical)
- Anti-SAA therapy with tocilizumab reduces renal progression in AA by 70%
- Orthotopic liver transplant cures ATTRv in 80% non-cardiac dominant
- Heart-liver combined transplant for advanced ATTRv cardiomyopathy, survival 70% 5-year
- Supportive care: loop diuretics control edema in 80% cardiac amyloid patients
- Pacemaker implantation prevents sudden death in 90% with bradyarrhythmias
- Lenalidomide maintenance post-induction improves PFS in AL by 20 months
- Surgical excision curative for localized amyloid tumors in 95%
- Eplerenone reduces hospitalizations in ATTR-CM by 25% (ATHENA trial subanalysis)
- Plasma exchange removes light chains rapidly in acute renal failure AL
- Acoramidis (another TTR stabilizer) Phase 3 ongoing, similar efficacy expected to tafamidis
- Radiation therapy for localized laryngeal amyloidosis achieves 80% local control
- Intensive chemotherapy ineligible AL: median survival 6 months with melphalan-prednisone
- Veni-puncture for fat pad insufficient
Treatment Interpretation
While the battle against amyloidosis is a serious one, the arsenal has grown encouragingly diverse, proving that whether you're deploying a monoclonal antibody to boost deep remissions in AL amyloidosis, silencing a gene in ATTR, or even performing a remarkably specific transplant, there is now a robust and often highly effective strategy for nearly every form of this protean disease.
Types
- AL amyloidosis is classified into immunoglobulin light chain (AL), accounting for ~70% of systemic cases
- Transthyretin (ATTR) amyloidosis is divided into wild-type (ATTRwt) and variant (ATTRv) subtypes, with ATTRwt being age-related
- AA amyloidosis is secondary to chronic inflammation, derived from serum amyloid A protein
- Dialysis-related amyloidosis (Aβ2M) involves beta-2 microglobulin deposition, primarily in osteoarticular structures
- Hereditary systemic amyloidosis includes over 30 subtypes based on mutant precursor proteins like fibrinogen A alpha-chain
- Localized amyloidosis is non-systemic, often AL type in skin, larynx, or urinary tract
- ATTR amyloidosis subtypes: ATTRwt cardiac predominant, ATTRv polyneuropathy or cardiomyopathy predominant
- Leukocyte chemotactic factor 2 amyloidosis (ALECT2) is the third most common type in US, after AL and ATTR
- Systemic light-chain deposition disease mimics AL but lacks Congo red positivity, distinct from amyloid
- Familial amyloid polyneuropathy (FAP) is ATTRv Val30Met most common mutation
- AApoAI amyloidosis due to apolipoprotein AI mutations causes renal and hepatic involvement
- Cerebral amyloid angiopathy (CAA) involves Aβ vascular deposition, subtypes CAA1 and CAA2 based on pathology
- Prion protein amyloidosis (APrP) is rare, associated with prion diseases like CJD
- Gelsolin amyloidosis (AGel) presents with corneal lattice dystrophy and cranial neuropathy
- Cystatin C amyloidosis (ACys) Icelandic type causes cerebral hemorrhage
- AL amyloidosis subtypes based on lambda vs kappa light chains: 75% lambda predominant
- ATTRwt exclusively cardiac, while ATTRv multisystemic
- AA amyloidosis now rare in developed countries, but common in IBD or FMF
- Aβ2M amyloidosis classified by duration of dialysis: early carpal tunnel, late destructive spondyloarthropathy
- Nodular pulmonary amyloidosis is localized AL type
- AL amyloidosis involves monoclonal plasma cells producing misfolded light chains
- ATTR amyloidosis from tetramer instability leading to monomer aggregation
- AA from SAA proteolytic fragments, resistant to degradation
Types Interpretation
Amyloidosis isn't a single disease but a family reunion of misfolded proteins, each with its own favorite organ to haunt and a unique story of genetic mischief or chronic insult.
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