Amyloidosis

From soluble protein to fibril

• Amyloidogenesis requires a precursor that is either structurally unstable (a mutant transthyretin, a clonal immunoglobulin light chain with an amyloidogenic variable region) or present in excess for a prolonged period (serum amyloid A during years of uncontrolled inflammation, beta-2-microglobulin in long-term dialysis)
• The native protein partially unfolds, exposing hydrophobic surfaces; monomers self-associate into oligomers, then protofilaments, then mature fibrils 7.5-10 nm wide arranged in a cross-beta configuration perpendicular to the fibril axis
• This quaternary structure is remarkably protease-resistant, which is why deposits accumulate rather than turn over, and why clinical improvement after successful therapy is slow (months to years) even when new fibril production stops immediately
• Fibrils incorporate universal accessory molecules — serum amyloid P component (SAP), apolipoprotein E, glycosaminoglycans — that stabilize the deposit and shield it from clearance. SAP is the basis of SAP scintigraphy and of experimental anti-SAP antibody therapy

How deposits injure organs

• Mechanical infiltration: fibrils expand the interstitium, separating myocytes and stiffening the ventricle, encasing glomeruli and nerves. This accounts for restrictive physiology and for the paradox that the heart is thick but not hypertrophied — the extra thickness is deposit, not muscle
• Direct proteotoxicity: this is specific to AL. Circulating light chains and their prefibrillar oligomers impair cardiomyocyte lysosomal function and generate oxidative stress before deposits are large. It explains the central clinical asymmetry of amyloidosis — a patient with AL and modest wall thickening can be far sicker than a patient with ATTR and a much thicker heart, and it explains why AL patients can improve rapidly once light chain production is suppressed
• Adsorption of circulating factors: amyloid fibrils bind factor X (acquired factor X deficiency and bleeding) and bind digoxin and calcium channel blockers (drug accumulation and toxicity at ordinary doses)
• Vascular fragility: perivascular deposition makes small vessels friable — the mechanism behind periorbital purpura appearing after a cough, a Valsalva, or the pressure of an eyelid rub

• Precursor: a monoclonal immunoglobulin light chain, produced by a small, usually indolent clonal plasma cell population in the marrow. Lambda outnumbers kappa roughly 3:1, the reverse of the normal ratio
• The clone is typically small (median marrow plasma cells ~7-10%). AL is a disease of protein quality, not tumor bulk — most patients do not meet criteria for multiple myeloma
• Arises de novo, or from MGUS (which carries roughly a 1% per year risk of progression to any plasma cell malignancy), or alongside overt myeloma or Waldenström macroglobulinemia
• Median age at diagnosis ~63 years; slight male predominance

AA (serum amyloid A / "secondary") amyloidosis

• Precursor: serum amyloid A, an apolipoprotein and acute-phase reactant synthesized by hepatocytes under IL-1, IL-6 and TNF-alpha drive. Sustained overproduction over years is required — this is a complication of uncontrolled, not merely present, inflammation
• Chronic inflammatory disease: rheumatoid arthritis (the classic Western cause), juvenile idiopathic arthritis, ankylosing spondylitis, psoriatic arthritis, Crohn disease
• Chronic infection: osteomyelitis, bronchiectasis, tuberculosis, leprosy, chronically infected pressure ulcers, and subcutaneous ("skin popping") injection drug use
• Hereditary periodic fever syndromes, above all familial Mediterranean fever — where amyloidosis is the leading cause of death in untreated patients and is prevented by lifelong colchicine
• Chronic malignancy, classically renal cell carcinoma and Hodgkin lymphoma
• Incidence has fallen substantially in the biologic era as inflammatory arthritis is better suppressed

ATTR (transthyretin) amyloidosis

• Precursor: transthyretin, a liver-synthesized tetramer that transports thyroxine and retinol-binding protein (hence its old name, prealbumin). Tetramer dissociation into monomers is the rate-limiting step of fibril formation — the pharmacologic target of stabilizer drugs
• Wild-type ATTR (ATTRwt): no mutation; age-related destabilization. Overwhelmingly men over 70. Presents as cardiac disease, often preceded by years of orthopedic complaints
• Variant/hereditary ATTR (ATTRv): autosomal dominant point mutations, over 130 described, with age-dependent penetrance
• Val122Ile (p.V142I) — carried by approximately 3-4% of Black Americans of West African ancestry; predominantly cardiac, presenting after age 60. Vastly underdiagnosed
• Val30Met (p.V50M) — predominantly neuropathic (familial amyloid polyneuropathy); endemic foci in Portugal, Sweden, Japan and Brazil, with early onset and high penetrance in the Portuguese clusters
• Thr60Ala — Irish/Appalachian; mixed cardiac and neurologic phenotype

Abeta-2-microglobulin (dialysis-related) amyloidosis

• Precursor: beta-2-microglobulin, the light chain of MHC class I, normally cleared by the kidney and poorly removed by older low-flux dialysis membranes
• Requires long dialysis vintage (usually >5-10 years). Deposits are osteoarticular, not visceral
• Incidence has fallen markedly with high-flux and high-cutoff membranes and earlier transplantation

Other precursors worth knowing

• Abeta (from amyloid precursor protein): senile plaques of Alzheimer disease; in vessel walls, cerebral amyloid angiopathy causing lobar intracerebral hemorrhage in the elderly
• IAPP / amylin: islet amyloid in type 2 diabetes mellitus, co-secreted with insulin
• Calcitonin (ACal): stromal amyloid within medullary thyroid carcinoma
• Atrial natriuretic peptide (AANF): isolated atrial amyloidosis in chronic atrial fibrillation and the aging heart
• Prion protein (PrP): spongiform encephalopathies
• ALECT2 (leukocyte chemotactic factor 2): a renal-limited amyloid disproportionately affecting patients of Mexican and Native American ancestry — an important non-AL cause of amyloid on kidney biopsy
• AApoAI, AFib (fibrinogen A alpha-chain): hereditary, predominantly renal

Cardiac (AL ~75%, ATTRwt ~100%, AA uncommon)

• Heart failure with preserved ejection fraction and a strikingly stiff, non-dilated ventricle: elevated JVP, hepatic congestion, ascites and peripheral edema dominate over pulmonary edema in advanced disease
• Exertional dyspnea and fatigue with poor exercise tolerance out of proportion to the echo
• Hypotension, or normalization of previously hypertensive blood pressure — a patient whose antihypertensives are being withdrawn one by one is a classic and often-missed presentation
• Syncope: orthostatic (autonomic neuropathy), exertional (fixed low stroke volume), or arrhythmic
• Atrial fibrillation is common; atrial mechanical failure produces intracavitary thrombus even in sinus rhythm
• Conduction disease, low-output syndrome, and sudden death — frequently by pulseless electrical activity rather than a shockable rhythm

Renal (AL ~60-70%, AA the dominant organ, ALECT2, AFib)

• Nephrotic-range proteinuria (albuminuric) with a bland urinary sediment — this is the single most useful renal discriminator. Dysmorphic red cells and RBC casts point away from amyloid and toward glomerulonephritis
• Progressive decline in GFR, hypoalbuminemia, anasarca, hyperlipidemia
• Kidneys are typically normal-sized or enlarged despite advancing renal failure
• ATTR rarely causes clinically significant renal disease — proteinuria in a patient with amyloid points to AL, AA or a hereditary non-TTR type

Neurologic

• Length-dependent, painful small-fiber polyneuropathy: burning feet, loss of pinprick and temperature first, progressing proximally, later with motor involvement. Prominent in AL and in ATTRv
• Autonomic neuropathy: orthostatic hypotension, early satiety and gastroparesis, alternating diarrhea and constipation, erectile dysfunction, anhidrosis. The combination of orthostatic hypotension and heart failure is highly suggestive
• Bilateral carpal tunnel syndrome from median nerve compression by tenosynovial deposits — in ATTRwt it precedes cardiac presentation by a median of 5-10 years and is the earliest actionable clue in the whole disease

Musculoskeletal and soft tissue

• Lumbar spinal stenosis, spontaneous biceps tendon rupture ("Popeye sign"), and rotator cuff disease — the ATTRwt orthopedic triad alongside carpal tunnel
• Macroglossia with lateral dental indentations: seen in 10-20% of AL and essentially never in ATTR or AA. Effectively diagnostic of AL when present, and may cause dysphagia, dysarthria and obstructive sleep apnea
• Shoulder pad sign: firm periarticular soft tissue enlargement
• Dialysis-related disease: carpal tunnel, scapulohumeral periarthritis, destructive spondyloarthropathy and subchondral bone cysts

Skin, hematologic and gastrointestinal

• Periorbital purpura ("raccoon eyes"), and purpura in skin folds, appearing after minimal strain — vascular fragility plus factor X deficiency. Like macroglossia, it points specifically to AL
• Acquired factor X deficiency from adsorption onto fibrils: prolonged PT and aPTT correcting on mixing, with bleeding disproportionate to the platelet count
• Hepatomegaly with a cholestatic pattern (elevated alkaline phosphatase, near-normal transaminases); splenomegaly with hyposplenism and Howell-Jolly bodies. Hepatosplenomegaly is prominent in AA
• GI: malabsorption, protein-losing enteropathy, bleeding, dysmotility, and rarely intestinal pseudo-obstruction

Step 1 — Screen for a plasma cell clone (do this first, always)

• Order all three together: serum immunofixation electrophoresis, urine immunofixation electrophoresis, and the serum free light chain assay. Combined sensitivity for AL exceeds 98%
• Serum protein electrophoresis alone is inadequate — the amyloidogenic light chain is often too small to raise a visible M-spike
• An abnormal free light chain ratio with an elevated involved chain, or the difference between involved and uninvolved chains (dFLC), is the quantity followed for treatment response. Interpret the ratio with care in renal failure, which raises both chains
• A monoclonal protein does not prove AL: MGUS is present in 3-5% of people over 70, exactly the population that develops ATTRwt. Coexistence is common and is the reason for step 3

Step 2 — Confirm amyloid histologically

• Congo red stain shows salmon-pink deposits on light microscopy and, under cross-polarized light, apple-green birefringence — the defining finding
• Electron microscopy: randomly oriented, non-branching 7.5-10 nm fibrils
• Least invasive sampling: abdominal subcutaneous fat pad aspirate (sensitivity ~75-80% in AL, but only ~15-45% in ATTR) plus bone marrow biopsy; the two together reach roughly 90% in AL. A negative fat pad never excludes amyloidosis
• Affected-organ biopsy (kidney, heart, nerve, liver) approaches 100% sensitivity when screening biopsies are negative and suspicion remains. Endomyocardial biopsy is essentially 100% sensitive for cardiac involvement

Step 3 — Type the fibril (never assume)

• Mass spectrometry-based proteomics on laser-capture microdissected deposits is the gold standard and is available at referral centers
• Immunohistochemistry is unreliable for AL — background immunoglobulin staining produces both false positives and false negatives — though it performs adequately for ATTR and AA
• TTR gene sequencing in every ATTR patient, to separate variant from wild-type. This changes prognosis, drug choice, and triggers cascade genetic counselling and screening of first-degree relatives

Cardiac evaluation

• ECG: low QRS voltage, or voltage that is merely normal in the presence of markedly thickened walls — the voltage-to-mass mismatch, present in roughly half of patients (more often in AL than ATTR). Pseudoinfarct pattern with poor anterior R-wave progression; AV block; atrial fibrillation. Frank low voltage is helpful when present and its absence excludes nothing
• Echocardiography: increased biventricular wall thickness with a non-dilated cavity, biatrial enlargement, thickened valves and interatrial septum, small pericardial effusion, restrictive filling. The granular sparkling texture is classic but neither sensitive nor specific on modern harmonic imaging
• Apical sparing of longitudinal strain — the "cherry on top" bull's-eye pattern, with relative preservation of apical strain against impaired basal and mid strain — is a strong and readily obtained clue that distinguishes infiltration from hypertensive hypertrophy and from hypertrophic cardiomyopathy
• Cardiac MRI: diffuse, often subendocardial or transmural late gadolinium enhancement that does not respect coronary territories, abnormal gadolinium kinetics with difficulty nulling the myocardium, and a markedly elevated extracellular volume fraction
• Biomarkers: NT-proBNP and high-sensitivity troponin are elevated disproportionately to symptoms and drive the Mayo staging systems (troponin T, NT-proBNP and dFLC in the 2012 revision), which are the strongest prognostic tools in AL

Bone-avid scintigraphy — and its one absolute prerequisite

• 99mTc-PYP, -DPD or -HMDP scintigraphy shows myocardial uptake in ATTR. Perugini grade 2-3 uptake, or a heart-to-contralateral-lung ratio ≥1.5 at 1 hour, in a patient with a negative monoclonal protein screen on all three assays, establishes ATTR cardiac amyloidosis non-invasively with specificity approaching 100% — one of the few instances in medicine where imaging replaces biopsy for an infiltrative disease
• The prerequisite is not optional. Roughly 20-40% of AL hearts also take up tracer. Calling a positive scan "ATTR" without excluding a plasma cell clone misdiagnoses a patient whose untreated median survival may be months, and delays the chemotherapy that would have saved them
• Bone scintigraphy is insensitive for AL and must not be used to exclude it

AL amyloidosis — suppress the clone, urgently

• Treatment targets the plasma cell clone; the goal is a deep and rapid hematologic response, ideally dFLC below 10 mg/L, because organ recovery depends on stopping the supply of toxic light chains
• Daratumumab plus bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) is standard first-line therapy for newly diagnosed AL, having shown substantially higher complete hematologic and cardiac response rates than VCd alone in the ANDROMEDA trial
• Autologous stem cell transplantation remains an option for the minority who are transplant-eligible — adequate performance status, limited cardiac involvement, preserved systolic blood pressure. Transplant-related mortality is high in cardiac amyloidosis and eligibility must be assessed by an experienced center
• Response is tracked by serial dFLC and NT-proBNP; organ response lags hematologic response by many months
• Referral to a specialist amyloidosis center measurably improves outcomes and should not be delayed for diagnostic completeness

ATTR amyloidosis — stabilize the tetramer or silence the gene

• Tafamidis, a TTR stabilizer, reduced all-cause mortality and cardiovascular hospitalization in ATTR cardiomyopathy (ATTR-ACT) and is indicated in both wild-type and variant cardiac disease
• Acoramidis, a near-complete stabilizer, showed benefit on a hierarchical clinical endpoint in ATTRibute-CM and is an alternative oral option
• Gene silencers suppress hepatic TTR production: patisiran and vutrisiran (siRNA) and inotersen and eplontersen (antisense oligonucleotides). Vutrisiran reduced mortality and cardiovascular events in ATTR cardiomyopathy in HELIOS-B; patisiran and vutrisiran improved neuropathy endpoints in hereditary ATTR polyneuropathy (APOLLO, HELIOS-A). Inotersen requires monitoring for thrombocytopenia and glomerulonephritis
• Diflunisal is an inexpensive off-label stabilizer, limited by NSAID effects on renal function, fluid retention and bleeding
• Orthotopic liver transplantation — historically curative-in-principle for early Val30Met disease by removing the source of variant TTR — has largely been superseded by silencers, and does not stop wild-type deposition on an already-seeded heart
• CRISPR-based in vivo knockout of hepatic TTR (nex-z) is in late-phase trials
• Earlier treatment yields better outcomes; the therapeutic goal is preventing further deposition, not reversing existing disease

AA amyloidosis — extinguish the inflammation

• Control the underlying driver so that serum amyloid A returns to normal; SAA level is the target of therapy and correlates with renal outcome
• Tocilizumab (anti-IL-6 receptor) and TNF inhibitors in rheumatoid and other inflammatory arthritis; IL-1 blockade in autoinflammatory syndromes
• Colchicine in familial Mediterranean fever both treats attacks and prevents amyloidosis — one of the clearest examples of primary prevention of an amyloid disease
• Antimicrobial or surgical eradication of chronic infection; resection of an amyloid-driving tumor

Dialysis-related amyloidosis

• High-flux or high-cutoff membranes and hemodiafiltration reduce beta-2-microglobulin burden
• Kidney transplantation halts progression and relieves symptoms; established osteoarticular deposits persist

Supportive care in cardiac amyloidosis — the pharmacology is inverted

• Loop diuretics, often at high doses and combined with an aldosterone antagonist, are the mainstay of congestion management. Volume status is a narrow window: the stiff ventricle is preload-dependent, and over-diuresis causes hypotension and prerenal failure as readily as under-diuresis causes congestion
• Calcium channel blockers (verapamil, diltiazem, nifedipine) should be avoided — they bind amyloid fibrils, accumulate, and cause profound hypotension and negative inotropy
• Digoxin binds fibrils and has a narrow margin; classically avoided, and if used at all it must be at low dose with close monitoring
• Beta blockers are frequently poorly tolerated: cardiac output in a fixed-stroke-volume ventricle is rate-dependent, so slowing the heart lowers output. Reduce or withdraw if hypotension or fatigue develops
• ACE inhibitors and ARBs commonly precipitate symptomatic hypotension, particularly with concurrent autonomic neuropathy, and are frequently not tolerated
• Anticoagulation for atrial fibrillation regardless of CHA2DS2-VASc score, given the high thrombus risk from atrial mechanical failure; transesophageal echocardiography before cardioversion even after adequate anticoagulation
• Amiodarone is the preferred antiarrhythmic. ICDs have limited benefit because terminal events are often pulseless electrical activity rather than ventricular fibrillation
• Orthostatic hypotension: compression stockings, midodrine, droxidopa, and liberalized salt where congestion permits
• Advanced heart failure: cardiac transplantation is offered at selected centers, with AL patients requiring clone-directed therapy to prevent recurrence in the graft

• Progressive restrictive heart failure — the leading cause of death in both AL and ATTR cardiac disease, with recurrent hospitalizations for congestion and a narrowing therapeutic window between congestion and hypotension
• Sudden cardiac death, commonly by electromechanical dissociation, and high-grade AV block requiring pacing
• Intracardiac thrombus and systemic embolism, including in sinus rhythm
• End-stage renal disease from progressive glomerular deposition, and the complications of the nephrotic syndrome: venous thromboembolism and renal vein thrombosis from urinary antithrombin loss, hypoalbuminemic anasarca, hyperlipidemia
• Acquired factor X deficiency with periprocedural and spontaneous bleeding; splenic amyloid causing functional hyposplenism and, rarely, atraumatic splenic rupture
• Disabling autonomic failure: refractory orthostatic hypotension, gastroparesis, malabsorption and severe weight loss
• Progressive painful sensorimotor neuropathy with ulceration and falls
• Airway compromise from macroglossia and obstructive sleep apnea
• Hepatic failure is uncommon despite massive hepatomegaly, but cholestasis with a rising alkaline phosphatase marks advanced disease
• Treatment-related: bortezomib peripheral neuropathy, daratumumab infusion reactions and hypogammaglobulinemia, high transplant-related mortality in cardiac AL, inotersen thrombocytopenia and glomerulonephritis
• Prognosis: untreated AL with advanced cardiac involvement (Mayo stage IV) has a median survival measured in months, while patients achieving a complete hematologic response may live decades. Untreated ATTRwt cardiomyopathy has a median survival of roughly 3.5 years from diagnosis, and untreated Val122Ile disease about 2.5 years — both meaningfully extended by stabilizer and silencer therapy

• Congo red with apple-green birefringence under cross-polarized light identifies amyloid of any type. It tells you the deposit is amyloid and nothing about which protein — typing requires mass spectrometry
• Heart failure with preserved EF, thick ventricular walls, and low or unimpressive ECG voltage is the voltage-to-mass mismatch. True hypertrophy raises voltage; infiltration does not
• Bilateral carpal tunnel syndrome in an older man, years before heart failure, is the earliest actionable clue to wild-type ATTR — as are spontaneous biceps tendon rupture and lumbar spinal stenosis
• Periorbital purpura and macroglossia are specific to AL and are essentially never seen in ATTR or AA. Either finding should trigger an immediate light chain screen
• Nephrotic-range proteinuria with a bland urinary sediment, particularly in a patient with long-standing rheumatoid arthritis, Crohn disease or chronic osteomyelitis, is AA amyloidosis until proven otherwise
• Screen with serum immunofixation, urine immunofixation and serum free light chains — all three. SPEP alone misses AL, and a positive bone scintigram means nothing until a plasma cell clone has been excluded
• A monoclonal gammopathy in an elderly patient does not make the amyloid AL. MGUS is common in exactly the age group that develops ATTRwt; coexistence is frequent and typing is mandatory
• Apical sparing of longitudinal strain ("cherry on top") separates infiltration from hypertensive heart disease and hypertrophic cardiomyopathy on echocardiography
• Avoid calcium channel blockers and be very cautious with digoxin — both bind amyloid fibrils and accumulate. Beta blockers, ACE inhibitors and ARBs are frequently not tolerated. Amyloid heart failure is one of the few settings where standard heart failure pharmacotherapy is contraindicated rather than beneficial
• A negative abdominal fat pad aspirate does not exclude amyloidosis, and is particularly insensitive in ATTR — proceed to organ biopsy when suspicion is high
• Val122Ile TTR is carried by 3-4% of Black Americans; consider hereditary ATTR in any Black patient over 60 with unexplained HFpEF, and sequence TTR in every ATTR patient to trigger family screening
• Colchicine prevents amyloidosis in familial Mediterranean fever — lifelong adherence is what protects the kidney
• Amyloid may be the answer when antihypertensives are being withdrawn because a previously hypertensive patient has become normotensive or hypotensive as heart failure advances
• Acquired factor X deficiency explains bleeding with a normal platelet count; check factor X before any biopsy in suspected AL
• Beta-2-microglobulin amyloidosis follows long dialysis vintage and is osteoarticular — carpal tunnel, shoulder pain and destructive spondyloarthropathy — not visceral