Amyloidosis

Amyloidosis is not a single disease but a family of disorders that share one mechanism: a normally soluble precursor protein misfolds into an abnormal beta-pleated-sheet conformation, aggregates into insoluble amyloid fibrils, and deposits extracellularly in tissue, where it progressively disrupts organ structure and function. More than 30 different precursor proteins can produce systemic amyloidosis, but two account for the overwhelming majority of clinically important, pharmacotherapy-actionable disease: AL amyloidosis (immunoglobulin free light chain, produced by a clonal population of plasma cells) and ATTR amyloidosis (transthyretin, a liver-produced transport protein that misfolds either because of an inherited TTR gene variant — hereditary, hATTR — or simply with age in a genetically normal protein — wild-type, wtATTR).^[1]

AL and ATTR are entirely different diseases and must never be treated as interchangeable "amyloidosis." AL is fundamentally a hematologic malignancy: the underlying plasma-cell clone is treated with anti-plasma-cell chemo-immunotherapy, essentially as multiple myeloma is, and untreated cardiac AL carries a median survival measured in months. ATTR is a protein-misfolding disease with no malignant clone to eradicate: treatment instead stabilizes the transthyretin tetramer against misfolding (a TTR stabilizer) or reduces hepatic production of transthyretin altogether (an RNA-silencing agent). Confirming which disease is present — before starting either kind of therapy — is the single most consequential decision point in this chapter, and it is the organizing principle behind every section that follows.

ATTR-CM (cardiac phenotype — wild-type or hereditary)

Almost exclusively a disease of infiltrative heart failure with preserved ejection fraction, typically in men over 70 for wtATTR. The clinical clues that separate it from ordinary HFpEF are frequently present years before the cardiac diagnosis is made and are easy to miss if they are not specifically asked about:

• Bilateral carpal tunnel syndrome, especially if it required surgical release — often precedes the cardiac diagnosis by 5-10 years.
• Lumbar spinal stenosis, and a history of biceps tendon rupture.
• Low-flow, low-gradient severe aortic stenosis with a discordant echocardiogram.
• Unexplained left ventricular hypertrophy out of proportion to any history of hypertension, together with unexpectedly low or low-normal QRS voltage on ECG.
• An echocardiographic "apical sparing" pattern of reduced longitudinal strain (a bull's-eye "cherry on top" appearance).
• A falling, rather than rising, antihypertensive requirement over time, or new intolerance of a previously well-tolerated blood pressure medication — reflects the fixed stroke volume of a restrictive, infiltrated ventricle rather than improving cardiovascular health.

hATTR polyneuropathy (hereditary only)

A progressive sensorimotor and autonomic polyneuropathy, often with a family history consistent with autosomal dominant inheritance — though penetrance is variable and age-related, so a negative family history does not exclude it. Autonomic features (orthostatic hypotension, alternating diarrhea and constipation, early satiety, erectile dysfunction, unexplained weight loss) are frequently present alongside the sensorimotor findings and are an important clue distinguishing it from a routine diabetic or idiopathic polyneuropathy. Cardiac and neurologic involvement commonly coexist as a "mixed phenotype," which changes the treatment choice (see Choose Initial Treatment).^[2]

AL amyloidosis

• An underlying clonal plasma-cell disorder, ranging from an otherwise-asymptomatic clone to overt multiple myeloma — a plasma-cell clone is present in essentially every AL patient, even though most do not meet criteria for myeloma itself.
• Age typically in the 60s at diagnosis; AL is uncommon before age 40.
• No major heritable component to AL itself — unlike ATTR, first-degree relatives are not placed at increased risk by an AL diagnosis alone.

Hereditary ATTR (hATTR)

• A pathogenic TTR gene variant, inherited in an autosomal dominant pattern with variable, age-related penetrance — a carrier may not develop symptoms until decades after an affected parent did, or at all.
• Specific variants cluster geographically and ethnically: Val30Met is endemic in parts of Portugal, Sweden, and Japan; Val122Ile is disproportionately carried by people of West African descent, including in North America, and preferentially produces a cardiac-predominant phenotype.
• A first-degree relative with confirmed hATTR — an indication for genetic counselling and cascade testing regardless of the relative's own symptom status.

Wild-type ATTR (wtATTR)

• Age over 70, and male sex — wtATTR is rare before 60 and disproportionately affects men.
• A history of bilateral carpal tunnel syndrome or lumbar spinal stenosis, particularly if surgery was required for either.
• Low-flow, low-gradient severe aortic stenosis being worked up for valve replacement — a recognized overlap population worth specifically screening.

AL vs ATTR — a comparison that changes everything about treatment

Diagnostic pathway

Always rule out AL first, because it is the more rapidly fatal of the two and treating a patient for presumed ATTR while an underlying plasma-cell clone goes unaddressed is a dangerous, avoidable delay. Send serum free light chains with the kappa/lambda ratio, SPEP with immunofixation, and UPEP with immunofixation as the initial screen; a genuinely negative panel across all three makes AL unlikely.^[1]

If the light chain screen is abnormal, proceed to tissue biopsy — a fat pad aspirate is minimally invasive and reasonably sensitive as the first-line site — with Congo red staining showing the classic apple-green birefringence under polarized light. Confirm the specific amyloid subtype by mass spectrometry-based proteomic typing wherever it is available, rather than relying on immunohistochemistry alone: a coincidental plasma-cell clone (for example an incidental MGUS) does not guarantee the deposited amyloid is actually AL type, and misclassifying the subtype directs the patient toward entirely the wrong treatment.

If the light chain screen is negative, proceed to technetium-99m pyrophosphate (PYP) cardiac scintigraphy. Grade 2 or 3 cardiac uptake on PYP, combined with a genuinely negative light chain screen, has a positive predictive value approaching 100% for ATTR cardiac amyloidosis and allows a confident non-biopsy diagnosis in this setting.^[3] Once ATTR is confirmed, send TTR gene sequencing in every patient to distinguish hereditary from wild-type disease — this determines whether genetic counselling and family cascade testing are needed, and can also identify a mixed cardiac/neurologic phenotype that changes therapy selection.

Echocardiography and cardiac MRI findings suggestive of cardiac amyloidosis

• Increased ventricular wall thickness with a granular, "sparkling" myocardial texture.
• Reduced global longitudinal strain with relative apical sparing (the "cherry on top" bull's-eye pattern) — more specific than wall thickness alone.
• Small ventricular cavity size, biatrial enlargement, and a pericardial effusion.
• On cardiac MRI: diffuse subendocardial-to-transmural late gadolinium enhancement, and an elevated native T1 time / extracellular volume fraction.

Staging

Stage AL amyloidosis using the revised Mayo 2012 system, which assigns one point each for cardiac troponin T ≥0.025 ng/mL, NT-proBNP ≥1800 pg/mL, and a difference between involved and uninvolved free light chains (dFLC) ≥18 mg/dL — stage I (0 points) through stage IV (all three present) — to guide prognosis and how aggressively to sequence therapy.

Stage ATTR-CM using the UK National Amyloidosis Centre (NAC) system, based on NT-proBNP and eGFR: stage I (NT-proBNP ≤3,000 ng/L and eGFR ≥45 mL/min/1.73m²), stage III (NT-proBNP >3,000 ng/L and eGFR <45 mL/min/1.73m²), and stage II (neither stage I nor stage III criteria met).

Other studies to obtain

• 24-hour urine protein and creatinine clearance in every patient with AL, to quantify renal involvement and establish a baseline for monitoring.
• Serum and urine immunofixation plus a bone marrow biopsy with plasma-cell clonal assessment (including FISH cytogenetics) once AL is confirmed, to fully characterize the underlying plasma-cell disorder — arranged by the hematology team rather than ordered independently.

• Confirm the amyloid subtype (AL vs ATTR, and hereditary vs wild-type for ATTR) before starting any amyloid-specific therapy — the two diseases require entirely different drugs.
• AL: achieve a rapid, deep hematologic response — ideally a complete response or very good partial response with normalization of the involved free light chain — to halt ongoing amyloid deposition and give damaged organs the chance to recover.
• ATTR: slow disease progression by stabilizing the transthyretin tetramer against misfolding, or by reducing hepatic transthyretin production altogether, to preserve cardiac and neurologic function and reduce cardiovascular mortality and hospitalization.
• Manage heart failure symptoms carefully in a restrictive, infiltrated ventricle, where several conventional heart-failure drugs are poorly tolerated or relatively contraindicated (see Choose Initial Treatment).
• For hereditary ATTR, extend genetic counselling and cascade testing to at-risk relatives.
• Coordinate care through a multidisciplinary amyloidosis program (hematology, cardiology, neurology, genetics) rather than managing any single organ system in isolation.

• Refer every newly diagnosed patient to a multidisciplinary amyloidosis program (hematology, cardiology, neurology, and genetics working together) rather than managing organ systems in isolation.
• Genetic counselling and cascade testing for every confirmed hereditary TTR variant, extended to at-risk first-degree relatives regardless of their own symptom status.^[2]
• Sodium and fluid intake guidance individualized to volume status — amyloid hearts are simultaneously preload-dependent and volume-intolerant, so blanket fluid restriction can be as harmful as none at all.
• Compression stockings and physical counter-maneuvers for orthostatic hypotension, common in both AL with autonomic involvement and ATTR neuropathy.
• Cardiology assessment for conduction disease and arrhythmia risk — pacemaker implantation is common in ATTR given a high burden of conduction-system infiltration, though primary-prevention implantable defibrillators are used more selectively than in typical structural heart disease given the competing risk of pulseless electrical activity.
• Nutrition support for the weight loss and malnutrition common in advanced disease.
• Consider biopsy of tenosynovial tissue at the time of carpal tunnel release surgery in an at-risk patient (older man, bilateral symptoms) — an opportunistic amyloid-screening step increasingly recommended given how often ATTR-CM is preceded by carpal tunnel syndrome by years.

Pregnancy

AL amyloidosis in pregnancy is rare and high-risk; manage only through a specialized amyloidosis/high-risk obstetric program. None of daratumumab, bortezomib, cyclophosphamide, tafamidis, patisiran, or vutrisiran have adequate human pregnancy safety data, and several — cyclophosphamide in particular — are known or expected to cause fetal harm. Effective contraception is required during and, per each product's monograph, for a defined period after therapy for patients of reproductive potential. Discuss fertility preservation before starting cyclophosphamide-containing therapy where the treatment timeline allows it.

Breastfeeding

Data are limited or absent for essentially every amyloid-specific agent in this chapter. Daratumumab, bortezomib, cyclophosphamide, tafamidis, patisiran, and vutrisiran should each be assumed incompatible with breastfeeding unless a specialist has reviewed the current product monograph and determined otherwise for an individual patient.

Pediatrics

Systemic AL and ATTR amyloidosis, as described in this chapter, are diseases of adulthood; a genuinely amyloidogenic presentation in a child is rare and belongs in a specialized pediatric metabolic/genetics program rather than being extrapolated from this adult-focused chapter.

Older adults

wtATTR is, by definition, a disease of older adults, and most newly diagnosed AL patients are also in their 60s and 70s. Frailty materially affects tolerance of dara-VCd — dose-attenuate dexamethasone and reassess cyclophosphamide/bortezomib tolerance closely — and a full polypharmacy review is essential given how many standard cardiovascular drugs are poorly tolerated in cardiac amyloidosis (see Choose Initial Treatment).

Renal impairment

Bortezomib and cyclophosphamide typically require dose modification in significant renal impairment — follow the current product monograph and involve the treating hematology program rather than adjusting empirically. Daratumumab does not generally require renal dose adjustment. Data for patisiran and vutrisiran in severe renal impairment or dialysis are limited; verify against the current product monograph before use in this population.

AL amyloidosis

Track hematologic response with serial free light chains — aiming for normalization of the involved FLC, with a complete response or very good partial response as the goal — at least every cycle, alongside cardiac biomarkers (NT-proBNP, troponin) and 24-hour urine protein to track organ-level response, which typically lags the hematologic response by months. Repeat echocardiography roughly every 6-12 months to assess cardiac organ response once a hematologic response is established.

ATTR (all forms)

Follow the NT-proBNP trend, functional class, and 6-minute walk distance at each cardiology visit for ATTR-CM; use a validated neuropathy impairment score for hATTR-PN patients on RNA-silencing therapy. Check liver enzymes periodically, since mild transient transaminase elevation has been described with siRNA agents.

Vitamin A monitoring on an RNA-silencing agent

Transthyretin is the body's physiologic transport protein for retinol (vitamin A); both patisiran and vutrisiran lower serum vitamin A as an expected consequence of TTR knockdown. Supplement vitamin A at the recommended dietary allowance for patients on either agent, and counsel on and monitor for ocular symptoms of deficiency (night blindness, dry eyes) per the current product monograph.

Genetic follow-up

Reassess uptake of cascade genetic testing among at-risk relatives at routine follow-up for every confirmed hereditary ATTR family, and refer newly identified carriers for baseline cardiology/neurology assessment even before they are symptomatic.

1. Re-confirm the amyloid subtype. A patient not responding as expected to AL- or ATTR-directed therapy should have the original subtyping revisited (mass spectrometry-based proteomic typing, if not already done) — misclassification at diagnosis is the most dangerous cause of apparent treatment failure.
2. AL: if the hematologic response is inadequate after 1-2 cycles of dara-VCd, refer (or re-refer) to a specialized amyloidosis/hematology program for regimen modification, an alternative combination, or evaluation for autologous stem cell transplant in appropriately selected patients — this decision should not be made outside a specialized program.
3. ATTR: response to a TTR stabilizer or RNA-silencing agent is judged over months, not weeks — these drugs slow or halt progression rather than rapidly reversing existing organ damage, so a premature switch before an adequate treatment trial is a common and avoidable error. If genuine progression is confirmed on tafamidis, referral to the amyloidosis program to consider an RNA-silencing agent, or a combination/sequencing strategy, is appropriate.
4. Confirm adherence, and, for tafamidis specifically, confirm the patient is taking one formulation consistently (61 mg free acid or 80 mg meglumine) rather than an inadvertent mix or dose error.
5. Reassess for a second, unrelated process that could explain the lack of improvement — coexisting ischemic or valvular heart disease, or, rarely, two concurrent amyloid subtypes — rather than assuming the original diagnosis and treatment plan were simply wrong.

• Treating "amyloidosis" as one disease and using an ATTR-specific drug (tafamidis, patisiran, vutrisiran) in a patient who actually has AL, or vice versa — confirm the subtype first.
• Relying on immunohistochemistry alone to subtype a positive Congo red biopsy without mass spectrometry-based confirmation where it is available — an incidental plasma-cell clone does not guarantee the deposited amyloid is truly AL type.
• Prescribing tafamidis for hATTR polyneuropathy — it is Health Canada-approved for the cardiomyopathy indication only; use an RNA-silencing agent for the neuropathy-predominant phenotype instead.
• Assuming tafamidis meglumine 80 mg and tafamidis (free acid) 61 mg are interchangeable milligram-for-milligram, or combining them.
• Continuing digoxin or a nondihydropyridine calcium-channel blocker in a patient with cardiac amyloidosis.
• Pursuing conventional heart-failure target doses of an ACE inhibitor, ARB, or beta-blocker in advanced cardiac amyloidosis when the patient is becoming hypotensive — the fixed stroke volume of a restrictive ventricle, not undertreatment, is usually the limiting factor.
• Missing bilateral carpal tunnel syndrome or lumbar spinal stenosis as an early red flag for ATTR-CM, sometimes present 5-10 years before the cardiac diagnosis.
• Assuming Health Canada approval automatically means a drug is funded — verify current provincial/private formulary status for tafamidis and vutrisiran specifically, both of which carry real, documented Canadian access caveats.
• Forgetting vitamin A supplementation and monitoring in a patient on patisiran or vutrisiran.
• Expecting a rapid response to ATTR-directed therapy — these drugs are disease-stabilizing, not organ-restoring, and meaningful benefit is judged over months.
• Delaying referral to a multidisciplinary amyloidosis program while working through a general, non-specialist workup.

How to use this table: Doses are adult doses and require patient-specific confirmation (renal/hepatic function, weight, allergy history). Pediatric dosing is weight-based per the current product monograph unless stated. Drug pricing is intentionally omitted. Select any drug name to open its complete Pharmasist Drug Database page.

AL Amyloidosis — Plasma-Cell-Directed Therapy (Dara-VCd)

First-line regimen per the ANDROMEDA trial; 28-day cycles. Dose modification for cytopenias, neuropathy, or renal/hepatic impairment follows the individual product monograph and the treating hematology program.

ATTR Amyloidosis — Transthyretin-Targeted Therapy

Choice depends on phenotype (cardiomyopathy vs polyneuropathy vs mixed) and, for tafamidis specifically, on confirmed formulary access — see Choose Initial Treatment for the Canadian reimbursement caveats.

Cardiac Symptom Management — Use With Caution, or Avoid, in Cardiac Amyloidosis

Standard heart-failure pharmacotherapy is frequently poorly tolerated in a restrictive, infiltrated amyloid ventricle; several conventionally first-line agents are relatively contraindicated here specifically.