Amyloidosis: Causes, Symptoms, Diagnosis and Treatment — Overview, Diagnosis & Treatment Options | MyMedicPlus

Amyloidosis encompasses a group of diseases in which normally soluble proteins misfold into insoluble beta-pleated sheet fibrils that deposit extracellularly in organs and tissues, progressively disrupting structure and function. Over 30 distinct proteins have been identified as amyloidogenic; clinically, the three most important systemic amyloidoses are: AL amyloidosis (immunoglobulin light chain amyloidosis — plasma cell dyscrasia-related, the most common type in Western countries, approximately 4,500 new US cases annually); ATTR amyloidosis (transthyretin amyloidosis — either age-related wild-type ATTRwt or hereditary ATTRv from TTR gene mutations, estimated to be highly underdiagnosed with prevalence now recognized to be substantially higher than previously thought); and AA amyloidosis (serum amyloid A protein — complicating chronic inflammatory diseases, now rare in Western countries with effective rheumatological treatment). Heart, kidneys, peripheral nerves, liver, gastrointestinal tract, and soft tissues are the principal target organs. Amyloidosis is frequently diagnosed late due to the non-specificity of early symptoms and clinician under-recognition. Accurate subtype classification is essential before initiating therapy, as AL and ATTR treatments are completely different — mass spectrometry proteomics has emerged as the gold standard for tissue-based amyloid protein identification, with Congo red staining confirming amyloid presence. Modern targeted therapies have transformed outcomes for AL amyloidosis (daratumumab-VCd) and ATTR amyloidosis (tafamidis, patisiran/vutrisiran, inclisiran).

Each amyloidosis type has a distinct precursor protein and pathogenic mechanism. AL amyloidosis: clonal plasma cells (or rarely lymphoplasmacytic lymphoma) produce excessive abnormal immunoglobulin free light chains — lambda more often than kappa in a 3:2 ratio — that are inherently amyloidogenic due to their unique biophysical properties; the underlying plasma cell clone resembles smoldering myeloma in approximately 70% of cases; frank multiple myeloma underlies approximately 10-15%; Waldenström macroglobulinemia and CLL account for the remainder. ATTRwt amyloidosis (formerly senile cardiac amyloidosis): age-related spontaneous misfolding of wild-type transthyretin (TTR, a transport protein for thyroid hormone and retinol produced by the liver) into amyloid fibrils; prevalence increases steeply with age — detected in up to 25% of autopsies of individuals over age 80; strongly male-predominant (>90% of patients); increasingly recognized as a common cause of heart failure with preserved ejection fraction (HFpEF) in elderly men. ATTRv (hereditary ATTR) amyloidosis: over 130 pathogenic TTR point mutations identified worldwide, most important: Val122Ile (valine-to-isoleucine substitution at position 122 — present in approximately 3.4% of African Americans, causes predominantly cardiac ATTR); Val30Met (endemic in Portugal, Japan, and Sweden — causes familial amyloid polyneuropathy with early peripheral and autonomic neuropathy predominating). AA amyloidosis: chronic overproduction of acute-phase reactant serum amyloid A protein from any sustained inflammatory condition — rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever (FMF, MEFV gene pyrin mutations), psoriatic arthritis, and chronic infections (tuberculosis, osteomyelitis, bronchiectasis); predominantly affects the kidneys (nephrotic syndrome); now substantially less common in Western countries due to effective inflammatory disease treatment.

Amyloidosis presents with organ-specific manifestations determined by the amyloid type and predominant deposition site. AL amyloidosis — multisystem involvement: cardiac amyloidosis (50-70% of AL patients) with restrictive cardiomyopathy causing progressive dyspnea, exercise intolerance, and right heart failure with preserved ejection fraction; elevated cardiac biomarkers (NT-proBNP, troponin T/I) reflect myocardial injury; low voltage on ECG despite marked LV wall thickening on echocardiography is a classic diagnostic clue. Renal AL amyloidosis: heavy proteinuria (typically nephrotic range above 3.5 g/24h) causing hypoalbuminemia, marked bilateral ankle edema, periorbital edema, and progressive renal impairment. Autonomic neuropathy: orthostatic hypotension causing falls and syncope, diarrhea alternating with constipation, impotence, and urinary retention. Peripheral neuropathy: length-dependent sensorimotor neuropathy, often painful. Macroglossia (enlarged tongue with lateral scalloping) — pathognomonic AL finding present in approximately 10-15%. Bilateral periorbital purpura ('raccoon eyes') — pathognomonic, from capillary fragility due to amyloid infiltration of small blood vessels; occurs spontaneously or after minor Valsalva. Carpal tunnel syndrome (bilateral, often preceding diagnosis by years). Hepatomegaly (hepatic AL). ATTRwt cardiac amyloidosis: heart failure with preserved EF (HFpEF), particularly in men over 70; bilateral carpal tunnel syndrome (often preceding cardiac diagnosis by 5-10 years); lumbar spinal stenosis; and low-flow low-gradient aortic stenosis co-existing with ATTR deposits in the valve. ATTRv polyneuropathy: progressive bilateral length-dependent painful sensorimotor peripheral neuropathy; autonomic neuropathy (severe orthostasis, diarrhea, urinary dysfunction, impotence); cardiac amyloidosis in some variants. AA amyloidosis: nephrotic syndrome and progressive renal failure predominate; hepatosplenomegaly.

The diagnostic pathway begins with high clinical suspicion and tissue confirmation. Congo red staining on tissue biopsy (abdominal fat pad aspirate — simplest, sensitivity 60-80%; rectal biopsy — sensitivity 75-85%; affected organ biopsy — highest sensitivity) demonstrates characteristic apple-green birefringence under polarized light, confirming amyloid deposition. Mass spectrometry proteomics (laser microdissection of amyloid-laden tissue followed by liquid chromatography-tandem mass spectrometry) has replaced immunohistochemistry as the gold standard for amyloid protein subtype identification — sensitivity over 98% for all amyloid types. AL amyloidosis: serum protein electrophoresis (SPEP) with immunofixation; serum free light chain (FLC) assay with kappa/lambda ratio; 24-hour urine protein electrophoresis and immunofixation; bone marrow biopsy with plasma cell quantification and clonality assessment; echocardiography (granular sparkling appearance, concentric LV wall thickening, biatrial dilation, diastolic dysfunction, pericardial effusion); cardiac MRI (diffuse subendocardial late gadolinium enhancement); NT-proBNP and troponin T for cardiac staging (Mayo AL staging I-IV). ATTR cardiac amyloidosis: 99mTc-pyrophosphate (PYP) scintigraphy or 99mTc-DPD/HMDP — Grade 2-3 cardiac uptake (heart-to-contralateral ratio above 1.5) with negative serum and urine monoclonal protein provides non-invasive diagnosis of ATTR cardiac amyloidosis with sensitivity and specificity above 95%, eliminating need for cardiac biopsy in most patients. TTR gene sequencing distinguishes ATTRwt from ATTRv (mandatory in all ATTR patients). AA amyloidosis: serum amyloid A (SAA) levels; identification of underlying inflammatory disease; renal biopsy typically needed.

AL amyloidosis — treat the plasma cell clone to stop light chain production: daratumumab (anti-CD38 monoclonal antibody) plus VCd (bortezomib 1.3 mg/m2 SC days 1, 8, 15, 22; cyclophosphamide 300 mg/m2 po days 1, 8, 15, 22; dexamethasone 40 mg po days 1, 8, 15, 22, every 28 days) is the current first-line standard of care (ANDROMEDA trial: 78% hematologic complete response at 6 months, significantly superior to VCd alone; 60% cardiac and 53% renal organ responses). Hematologic complete response is the therapeutic goal — defined as normalization of FLC ratio and negative immunofixation. Autologous stem cell transplantation (ASCT) with high-dose melphalan conditioning for eligible patients (age below 65, performance status ECOG 0-2, cardiac stage I-II, NT-proBNP below 5,000 ng/L, troponin T below 75 ng/L) — achieves durable hematologic complete responses in approximately 40% of transplanted patients. ATTR amyloidosis — stabilize or silence TTR production: tafamidis meglumine 61 mg or tafamidis free acid 20 mg once daily for ATTR cardiac amyloidosis (ATTRwt and ATTRv) — ATTR-ACT trial: significant reduction in all-cause mortality (HR 0.70, p<0.0001) and CV hospitalization rates; indicated for NYHA Class I-III. Acoramidis (second-generation TTR kinetic stabilizer) approved by FDA in 2024 for ATTR cardiomyopathy with superior TTR stabilization. RNA silencing therapies for ATTRv polyneuropathy (primary indication): patisiran (siRNA, 0.3 mg/kg IV every 3 weeks, APOLLO trial: 56% reduction in neuropathy progression score) and vutrisiran (siRNA, 25 mg SC every 3 months — superior convenience, HELIOS-A trial); inotersen (antisense oligonucleotide, NEURO-TTR trial). CRISPR-Cas9 gene editing (NTLA-2001): single-dose treatment achieving durable near-complete TTR gene silencing in hereditary ATTR — promising early-phase data. AA amyloidosis: sustained suppression of the underlying inflammatory disease with biologics (anti-TNF, anti-IL-6, anti-IL-1 agents) or colchicine (for FMF) reduces SAA levels and prevents AA amyloid progression.

The prognosis for amyloidosis has been transformed by modern targeted therapies but depends heavily on subtype, degree of organ involvement at diagnosis, and speed of initiation of appropriate treatment. AL amyloidosis historically carried a median survival of approximately 12-18 months without treatment; early cardiac involvement was the dominant driver of mortality. With daratumumab-VCd (ANDROMEDA trial), hematologic complete response is now achieved in 78% of patients at 6 months, with cardiac organ responses in 60% and renal organ responses in 53%. Mayo AL staging (based on NT-proBNP, troponin T, and free light chain difference) stratifies survival from over 5 years for Stage I to approximately 5-7 months for Stage IIIb without prompt treatment. ATTR cardiomyopathy treated with tafamidis demonstrated significantly reduced cardiovascular mortality — ATTR-ACT trial showed a mortality hazard ratio of 0.70 over 30 months versus placebo; real-world data increasingly confirms extended survival. Wild-type ATTRwt cardiac amyloidosis without treatment has median survival of approximately 2-5 years from diagnosis; with tafamidis or acoramidis, survival is substantially extended. ATTRv polyneuropathy treated with patisiran or vutrisiran shows significant neuropathy stabilization or improvement in approximately 56-80% of patients, with halted disease progression in the majority. AA amyloidosis prognosis is determined by the success of controlling the underlying inflammatory disease — effective therapy normalizes serum amyloid A levels and can halt and even partially reverse renal amyloid progression. Factors adversely affecting prognosis include advanced cardiac staging, delayed diagnosis, severe renal impairment, and poor performance status at presentation. Early specialist referral before severe organ damage is critical across all amyloidosis subtypes.

AA amyloidosis can be prevented by achieving sustained control of the underlying chronic inflammatory disease using disease-modifying antirheumatic drugs (DMARDs), biologics (anti-TNF, IL-6 inhibitors), or colchicine (for Familial Mediterranean Fever) — chronic inflammation drives serum amyloid A overproduction and deposition. ATTRv amyloidosis in hereditary ATTR carriers: RNA-silencing therapies (vutrisiran, patisiran) and TTR stabilizers (tafamidis, acoramidis) are used prophylactically or early in disease to prevent progression. Genetic testing of family members of hereditary ATTR patients enables presymptomatic treatment. AL amyloidosis prevention is not currently achievable, but early treatment of the plasma cell clone before severe organ damage occurs markedly improves outcomes — making awareness of early signs critical.

Unexplained progressive breathlessness with preserved ejection fraction on echocardiography — particularly with thick-walled ventricles and a granular sparkling pattern — should raise suspicion for cardiac amyloidosis and warrants specialist cardiological evaluation. An older man with bilateral carpal tunnel syndrome, unexplained heart failure, and a thickened interventricular septum has a high probability of ATTR cardiac amyloidosis and should be referred. Bilateral periorbital purpura (bruising around the eyes) appearing without injury, macroglossia, or nephrotic-range proteinuria in a middle-aged adult are red flags for AL amyloidosis and require haematological evaluation. Peripheral neuropathy that is progressive, bilateral, involves both sensory and autonomic fibres, and is not explained by diabetes or B12 deficiency should prompt evaluation for hereditary ATTR amyloid neuropathy, particularly in individuals from endemic regions or with family history.