Amyloidosis
Misfolded protein deposition causing organ dysfunction. AL (light chain) is most common systemic type. Cardiac involvement = very poor prognosis. Classic clue: low voltage ECG + thick walls on echo. Diagnosis: Congo red stain with apple-green birefringence.
🔍 Overview
Overview
Amyloidosis is a group of diseases caused by extracellular deposition of misfolded proteins (amyloid fibrils) in tissues, leading to organ dysfunction. The protein type determines the disease subtype and treatment.
Major Types
- AL Amyloidosis (Light Chain) -from plasma cell dyscrasia. Most common systemic amyloidosis. Light chains (usually lambda) misfold and deposit. Related to multiple myeloma but most patients do NOT have overt myeloma.
- AA Amyloidosis -from serum amyloid A (SAA) protein, produced in chronic inflammation. Causes: RA, Crohn disease, familial Mediterranean fever (FMF), chronic infections. Predominantly affects kidneys.
- ATTR Amyloidosis (Transthyretin) -hereditary (mutant TTR) or wild-type (senile cardiac amyloidosis). Increasingly recognized as a cause of HFpEF in elderly patients.
Organ Involvement
- Heart -restrictive cardiomyopathy. Low voltage on ECG despite thick walls on echo (classic discordance). Diastolic dysfunction. Elevated troponin and BNP.
- Kidney -nephrotic syndrome (proteinuria, edema, hypoalbuminemia)
- Liver -hepatomegaly, elevated ALP
- Nerves -peripheral neuropathy (pain, numbness), autonomic neuropathy (orthostatic hypotension)
- GI -malabsorption, weight loss, GI bleeding
- Tongue -macroglossia (pathognomonic for AL amyloidosis)
Low voltage on ECG + thick walls on echo = think amyloidosis. In HCM, thick walls produce HIGH voltage. This voltage-mass discordance is a classic board question. The amyloid infiltrates the myocardium, increasing wall thickness but reducing electrical signal.
🚨 Management
AL Amyloidosis
- Treat the underlying plasma cell clone -goal is to eliminate the source of amyloidogenic light chains.
- First-line: Daratumumab + CyBorD (cyclophosphamide, bortezomib, dexamethasone). ANDROMEDA, NEJM 2021 -showed significantly higher hematologic complete response rate.
- Autologous stem cell transplant (SCT) -for eligible patients (typically younger, no significant cardiac involvement). Best long-term outcomes.
- Cardiac AL prognosis: Very poor -median survival 6 months untreated. With modern treatment, outcomes improving but cardiac involvement remains the dominant prognostic factor.
AA Amyloidosis
Treat the underlying inflammatory disease. Control RA, Crohn, FMF (colchicine for FMF). Reducing SAA levels can halt progression and even allow regression of amyloid deposits.
Supportive Care
- Heart failure: Diuretics -use cautiously, these patients are preload-dependent (restrictive physiology). Small changes in volume cause dramatic hemodynamic effects. Avoid digoxin (binds amyloid fibrils, causing toxicity at therapeutic levels).
- Orthostatic hypotension: Midodrine 5-10 mg TID, compression stockings, increased salt intake.
- Nephrotic syndrome: ACEi/ARB for proteinuria. Diuretics for edema.
🧪 Workup
Diagnosis
- Tissue biopsy with Congo red stain -apple-green birefringence under polarized light is diagnostic of amyloid.
- Fat pad aspirate -least invasive biopsy site. Sensitivity ~70-80% for AL. If negative but suspicion high, biopsy the affected organ.
- Bone marrow biopsy -to assess plasma cell clone in AL amyloidosis.
Typing the Amyloid
- SPEP / UPEP / serum free light chains -for AL amyloidosis. Free light chain ratio is abnormal in >95% of AL patients.
- SAA levels -for AA amyloidosis. Elevated in chronic inflammatory states.
- Mass spectrometry -gold standard for amyloid subtyping (laser microdissection + mass spec on biopsy tissue).
Cardiac Assessment
- Troponin and BNP/NT-proBNP -markedly elevated in cardiac amyloidosis. Used for staging (Mayo staging system).
- ECG -low voltage (limb leads <5mm) + pseudo-infarct pattern (Q waves without MI) are classic.
- Echocardiogram -thick walls + diastolic dysfunction. "Sparkling" or "granular" myocardium (sometimes described on older machines). Small LV cavity, biatrial enlargement.
- Cardiac MRI -characteristic diffuse subendocardial or transmural late gadolinium enhancement pattern. Global T1 elevation.
- Technetium pyrophosphate (PYP) scan -highly sensitive and specific for ATTR cardiac amyloidosis. Grade 2-3 uptake = diagnostic without biopsy.
💊 Medications
Medications
| Drug | Type | Dose | Notes |
|---|---|---|---|
| Daratumumab (Darzalex) AL 1ST LINE | AL | 16 mg/kg IV weekly x 8, then q2 weeks, then monthly | Anti-CD38 monoclonal antibody. Combined with CyBorD. ANDROMEDA, NEJM 2021 |
| Bortezomib (Velcade) | AL | 1.3 mg/m2 SQ weekly (part of CyBorD) | Proteasome inhibitor. Targets plasma cells. Peripheral neuropathy is dose-limiting toxicity. |
| Cyclophosphamide | AL | 300 mg/m2 PO weekly (part of CyBorD) | Alkylating agent. Dose adjust for renal function. |
| Dexamethasone | AL | 20-40 mg PO weekly (part of CyBorD) | Steroid component. Monitor glucose, infections. |
| Tafamidis (Vyndamax) | ATTR | 80 mg PO daily | TTR stabilizer for ATTR cardiac amyloidosis. Reduced mortality and CV hospitalization. ATTR-ACT, NEJM 2018 |
| Midodrine | Supportive | 5-10 mg PO TID | For orthostatic hypotension from autonomic neuropathy. Hold if supine BP >180. |
🏥 Rounds
Pimp Questions
❓ Why does amyloidosis cause low voltage on ECG despite thick walls on echo?
In HCM, the thick walls are due to myocyte hypertrophy, which increases electrical mass and produces high voltage. In amyloidosis, the thick walls are due to amyloid infiltration between myocytes -the amyloid protein is electrically inert and actually insulates the myocardium, reducing the electrical signal. This creates the classic voltage-mass discordance: thick walls + low voltage = amyloid (not HCM).
❓ Why is digoxin dangerous in cardiac amyloidosis?
Digoxin binds to amyloid fibrils in the myocardium, leading to tissue accumulation and toxicity even at "therapeutic" serum levels. Patients with cardiac amyloidosis are exquisitely sensitive to digoxin and can develop fatal arrhythmias. This is a classic pharmacology teaching point -always avoid digoxin in amyloid cardiomyopathy.
❓ What is the significance of macroglossia in amyloidosis?
Macroglossia is pathognomonic for AL amyloidosis -it does not occur in AA or ATTR types. Present in ~10-15% of AL patients. It is virtually diagnostic when seen in the right clinical context. Look for tooth indentations on the lateral tongue edges. Can also cause dysphagia and obstructive sleep apnea.
❓ How does the ANDROMEDA trial change AL amyloidosis treatment?
ANDROMEDA (NEJM 2021) showed that adding daratumumab (anti-CD38) to CyBorD (bortezomib, cyclophosphamide, dexamethasone) significantly improved hematologic complete response (53% vs 18%) and cardiac and renal organ response rates. Dara-CyBorD is now the standard first-line regimen for newly diagnosed AL amyloidosis.
Clinical Examples
📋 Case 1, AL Amyloidosis with Cardiac Involvement
Patient: 64M with progressive dyspnea, bilateral LE edema, and orthostatic hypotension. Echo: thick walls (IVS 16 mm), small LV cavity, diastolic dysfunction, EF 50%. ECG: low voltage + pseudo-infarct pattern. NT-proBNP 9200, troponin 0.18. Macroglossia on exam.
Key findings: Classic cardiac AL amyloidosis: thick walls + low voltage on ECG = pathognomonic discordance (hypertrophy causes high voltage, but amyloid infiltration causes low voltage). Macroglossia is virtually diagnostic for AL type.
Management:
- Fat pad aspirate or organ biopsy → Congo red stain (apple-green birefringence under polarized light)
- Mass spectrometry typing to confirm AL (vs ATTR), critical for treatment selection
- Dara-CyBorD: daratumumab + bortezomib + cyclophosphamide + dexamethasone (first-line per ANDROMEDA) ANDROMEDA, 2021
- Diuretics for volume overload, use cautiously (preload-dependent restrictive physiology). AVOID digoxin (binds to amyloid fibrils → toxicity at therapeutic levels)
- Midodrine for orthostatic hypotension (autonomic neuropathy from amyloid infiltration)
Teaching point: The ECG-echo discordance (low voltage + thick walls) is the signature finding of cardiac amyloidosis. HCM and hypertensive heart disease cause thick walls WITH high voltage. If the walls are thick but voltage is low → think amyloid.
📋 Case 2, ATTR Cardiac Amyloidosis (Wild-Type)
Patient: 82M with HFpEF refractory to standard therapy. History of bilateral carpal tunnel surgery, lumbar spinal stenosis. Echo: concentric LVH (IVS 15 mm), grade III diastolic dysfunction. Technetium pyrophosphate scan: grade 3 uptake. SPEP/sFLC normal.
Key findings: Wild-type ATTR (ATTRwt), transthyretin amyloidosis from age-related misfolding. No plasma cell dyscrasia (SPEP/sFLC normal). Tc-PYP scan grade 2-3 = diagnostic for ATTR without biopsy (if SPEP/sFLC negative). Bilateral carpal tunnel + spinal stenosis are early manifestations.
Management:
- Tafamidis 80 mg daily, TTR stabilizer, reduces mortality and HF hospitalization ATTR-ACT, 2018
- No chemotherapy needed (ATTR is not a plasma cell disorder, no clonal cells to target)
- Diuretics for congestion, careful volume management
- Genetic testing: rule out hereditary ATTR (TTR gene mutations, affects family screening and transplant eligibility)
- Avoid ACEi/ARB aggressively, often poorly tolerated due to restrictive physiology + autonomic dysfunction
Teaching point: ATTR is now recognized as a common cause of HFpEF in elderly men, prevalence may be 10-15% of HFpEF patients > 80. Bilateral carpal tunnel + HFpEF + thick walls should trigger Tc-PYP scan. Tafamidis is disease-modifying.
📋 Case 3, AL Amyloidosis with Nephrotic Syndrome
Patient: 58F with progressive LE edema, foamy urine. Albumin 1.8, 24h urine protein 8.2 g/day, Cr 1.6. sFLC: lambda 420 mg/L (elevated), ratio abnormal. Renal biopsy: Congo red positive in glomeruli and vessels.
Key findings: AL amyloidosis presenting as nephrotic syndrome (renal is the most common organ involved in AL). Lambda light chain predominance. Must assess cardiac involvement, asymptomatic cardiac amyloid can coexist.
Management:
- Cardiac biomarkers: NT-proBNP + troponin (Mayo staging, determines prognosis and treatment intensity)
- Echo + ECG to assess subclinical cardiac involvement
- Dara-CyBorD (standard first-line for AL amyloidosis regardless of organ involvement)
- Aggressive diuresis for nephrotic edema (furosemide + metolazone). ACEi/ARB for proteinuria reduction
- If young + fit + good cardiac function: consider autologous stem cell transplant after induction (high CR rates in selected patients)
Teaching point: In any patient with unexplained nephrotic syndrome + monoclonal protein, think AL amyloidosis. The combination of nephrotic-range proteinuria + abnormal sFLC ratio is the classic presentation. Always check cardiac biomarkers, occult cardiac involvement determines prognosis.
Sample Presentation
Mr. Franklin is a 62-year-old man presenting with 6 months of progressive dyspnea on exertion, lower extremity edema, and 15-lb weight loss. He also reports numbness/tingling in both feet and lightheadedness when standing. Exam: macroglossia, periorbital purpura, elevated JVP, bilateral pitting edema. Labs: troponin 0.15 (elevated), NT-proBNP 8,400 (markedly elevated), creatinine 1.8, albumin 2.1, 24h urine protein 5.2 g/day. ECG: low voltage + pseudo-infarct pattern. Echo: thick walls (IVS 16mm) + diastolic dysfunction + small LV cavity. Free kappa/lambda ratio markedly abnormal (lambda predominant). Fat pad biopsy: Congo red positive, apple-green birefringence under polarized light.
Key Points: Classic AL amyloidosis with multiorgan involvement -cardiac (restrictive CMP, low voltage + thick walls), renal (nephrotic syndrome), neurologic (peripheral and autonomic neuropathy), macroglossia (pathognomonic). Staging: elevated troponin + NT-proBNP = advanced cardiac involvement (Mayo Stage III). Start Dara-CyBorD. Diuretics for volume overload but use cautiously (preload-dependent). Midodrine for orthostatic hypotension. Avoid digoxin.
Monitoring
- Serum free light chains -q1-3 months during treatment. Hematologic response: normalization of free light chain ratio.
- NT-proBNP and troponin -cardiac biomarkers used for staging and monitoring organ response. Reduction indicates cardiac response.
- 24h urine protein -for renal involvement. Renal response: >50% reduction in proteinuria.
- Echocardiogram -q6-12 months. Monitor wall thickness, diastolic function, strain patterns.
- ALP -for hepatic involvement. Hepatic response: >50% decrease in ALP.
- Orthostatic vitals -for autonomic neuropathy monitoring.
- CBC, BMP -monitor for treatment toxicity (myelosuppression from chemo, renal function).
📋 Summary
Summary
What It Is
Misfolded protein deposits as insoluble fibrils and progressively stiffens organs. AL (light chain) is the commonest systemic type and comes from a clonal plasma cell disorder. ATTR is transthyretin, either hereditary or wild-type in older men. AA is serum amyloid A driven by chronic inflammation.
The Clue That Should Trigger the Thought
Low voltage on the ECG with thick walls on echo. In hypertrophic cardiomyopathy thick walls produce high voltage; here the myocardium is infiltrated rather than hypertrophied, so mass rises while voltage falls. That voltage-mass discordance is the single most useful bedside signal.
Other Presentations Worth Recognizing
Nephrotic-range proteinuria, heart failure with preserved ejection fraction, hepatomegaly out of proportion to liver tests, peripheral and autonomic neuropathy, and the specific signs: macroglossia and periorbital purpura, which are nearly exclusive to AL. Bilateral carpal tunnel syndrome years before the cardiac diagnosis is the classic early clue in ATTR.
Confirm With Tissue
Congo red staining with apple-green birefringence under polarized light. Abdominal fat pad aspirate is the least invasive first step; if negative and suspicion is high, biopsy the affected organ. Never stop at 'amyloid present', because the type determines the entire treatment.
Typing Is the Decision Point
Mass spectrometry on the tissue is the gold standard. Check serum and urine immunofixation with serum free light chains for a plasma cell clone. Assuming AL because a monoclonal protein is present is a real error: MGUS is common in the elderly and coexists with ATTR, and treating ATTR with chemotherapy helps nobody. A PYP scan diagnoses ATTR cardiac amyloid non-invasively once AL has been excluded.
Treat AL by Killing the Clone
Daratumumab added to CyBorD (cyclophosphamide, bortezomib, dexamethasone) is first line (ANDROMEDA). Autologous stem cell transplant in carefully selected patients. Response is tracked by the free light chain difference, not by symptoms, and organ recovery lags the hematologic response by months.
Treat ATTR by Stabilizing the Protein
Tafamidis 80 mg daily reduces mortality and cardiovascular hospitalization in ATTR cardiomyopathy (ATTR-ACT). Gene-silencing agents are used in hereditary ATTR polyneuropathy. Start early, because these agents stop further deposition but do not clear what is already there.
The Cardiac Drugs Behave Differently
Amyloid heart failure is a restrictive, preload-dependent physiology, so standard heart failure therapy can do harm. Beta blockers and ACE inhibitors are often poorly tolerated and cause hypotension. Avoid digoxin and calcium channel blockers, which bind to amyloid fibrils and are prone to toxicity. Diuretics are the mainstay. Cardiac involvement is the dominant prognostic factor, which is why staging uses troponin and NT-proBNP.
📄 One Pager
Text version
HEME / ONC · One Pager
Amyloidosis
Extracellular deposition of misfolded protein. Congo red proves it is amyloid, but the protein type is what determines the disease and the treatment, so typing the tissue is not an academic step, it is the whole decision.
The Subtypes Drive Everything
- AL (light chain): from a plasma cell dyscrasia. The most common systemic amyloidosis. Light chains, usually lambda, misfold and deposit. Related to multiple myeloma, but most patients do not have overt myeloma, so a normal marrow does not exclude it. Treatment targets the clone.
- ATTR (transthyretin), hereditary: mutant TTR. Genetic testing matters here because it changes family screening and transplant eligibility, not just the label.
- ATTR, wild-type (ATTRwt, senile cardiac amyloidosis): age-related TTR misfolding with no plasma cell clone. Increasingly recognized as a cause of HFpEF in elderly patients; prevalence may be 10–15% of HFpEF patients > 80. Bilateral carpal tunnel surgery and lumbar spinal stenosis are early manifestations that precede the heart failure by years.
- AA: from serum amyloid A (SAA) produced in chronic inflammation. Causes: RA, Crohn disease, familial Mediterranean fever, chronic infections. Predominantly affects the kidneys. Treatment is control of the inflammatory driver, not chemotherapy.
- Do not blur AL and ATTR. AL gets chemotherapy; ATTR has no clone to target and gets a TTR stabilizer. Getting this backwards means either useless chemotherapy or an untreated fatal plasma cell disease.
Organ Clues That Should Trigger the Thought
- Heart, restrictive cardiomyopathy: low voltage on ECG despite thick walls on echo, the classic voltage-mass discordance. In HCM and hypertensive heart disease, thick walls produce high voltage because the thickness is myocyte hypertrophy. In amyloid, the thickness is electrically inert protein infiltrating between myocytes, which insulates the myocardium.
- Kidney: nephrotic syndrome, proteinuria, edema, hypoalbuminemia. Unexplained nephrotic syndrome plus a monoclonal protein is AL until proven otherwise.
- Tongue, macroglossia: pathognomonic for AL, present in roughly 10–15% of AL patients and does not occur in AA or ATTR. Look for tooth indentations on the lateral tongue edges; it can also cause dysphagia and obstructive sleep apnea.
- Nerves: peripheral neuropathy (pain, numbness) and autonomic neuropathy (orthostatic hypotension). The orthostasis is not just deconditioning.
- Liver: hepatomegaly with elevated alkaline phosphatase.
- GI: malabsorption, weight loss, GI bleeding.
Diagnostic Sequence: Prove It, Then Type It
1
Prove amyloid is present: tissue biopsy with Congo red stain showing apple-green birefringence under polarized light. Start with fat pad aspirate, the least invasive site, sensitivity ~70–80% for AL. If it is negative and suspicion stays high, biopsy the affected organ, because a negative fat pad does not rule out disease.
2
Type the amyloid, this is the step that decides treatment. Mass spectrometry (laser microdissection plus mass spec on biopsy tissue) is the gold standard for subtyping.
3
Screen for the plasma cell clone: SPEP, UPEP, and serum free light chains. The free light chain ratio is abnormal in > 95% of AL patients, which is what makes a normal sFLC and SPEP so useful for pointing toward ATTR instead. Bone marrow biopsy assesses the clone in AL. Check SAA if the picture suggests AA.
4
Assess the heart in everyone, because occult cardiac involvement determines prognosis. Troponin and BNP/NT-proBNP are markedly elevated and are used for Mayo staging. ECG: low voltage (limb leads < 5 mm) plus pseudo-infarct pattern (Q waves without MI). Echo: thick walls, diastolic dysfunction, small LV cavity, biatrial enlargement, "sparkling" or granular myocardium. Cardiac MRI: diffuse subendocardial or transmural late gadolinium enhancement with global T1 elevation.
5
Technetium pyrophosphate (PYP) scan when ATTR is on the table: highly sensitive and specific for ATTR cardiac amyloidosis, and grade 2–3 uptake is diagnostic without biopsy. In hereditary versus wild-type ATTR, send TTR genetic testing, since a mutation changes family screening and transplant eligibility.
Key Drugs by Subtype
Daratumumab (Darzalex)AL first-line: 16 mg/kg IV weekly × 8, then q2 weeks, then monthly; anti-CD38, combined with CyBorD
Bortezomib (Velcade)AL: 1.3 mg/m² SQ weekly as part of CyBorD; proteasome inhibitor, peripheral neuropathy is dose-limiting
CyclophosphamideAL: 300 mg/m² PO weekly as part of CyBorD; dose adjust for renal function
DexamethasoneAL: 20–40 mg PO weekly as part of CyBorD; monitor glucose and infections
Tafamidis (Vyndamax)ATTR: 80 mg PO daily; TTR stabilizer that reduced mortality and CV hospitalization in ATTR cardiomyopathy
MidodrineSupportive: 5–10 mg PO TID for orthostatic hypotension from autonomic neuropathy; hold if supine BP > 180
ColchicineAA from familial Mediterranean fever; controlling the inflammatory driver lowers SAA
Autologous stem cell transplantAL, for eligible patients (typically younger, no significant cardiac involvement); best long-term outcomes
Monitoring
- Serum free light chains q1–3 months during treatment. Hematologic response means normalization of the free light chain ratio, and it moves before organ function does.
- NT-proBNP and troponin for staging and organ response; a reduction indicates cardiac response, the response that matters most for survival.
- 24h urine protein for renal involvement. Renal response is defined as a > 50% reduction in proteinuria.
- ALP for hepatic involvement; hepatic response is a > 50% decrease.
- Echocardiogram q6–12 months to track wall thickness, diastolic function, and strain patterns.
- Orthostatic vitals to follow autonomic neuropathy and titrate midodrine.
- CBC and BMP for treatment toxicity: myelosuppression from chemotherapy and renal function.
Pitfalls
- Digoxin in cardiac amyloidosis. It binds amyloid fibrils and accumulates in tissue, producing toxicity and potentially fatal arrhythmias at "therapeutic" serum levels. Avoid it entirely.
- Aggressive diuresis. Restrictive physiology makes these patients preload-dependent, so small volume changes cause dramatic hemodynamic effects. Diurese, but cautiously.
- Reading thick walls as HCM or hypertensive heart disease. Thick walls with low voltage is amyloid; thick walls with high voltage is hypertrophy.
- Skipping the typing step. Congo red only says "amyloid". Committing an ATTR patient to chemotherapy, or an AL patient to tafamidis alone, follows directly from that shortcut.
- Calling a PYP scan diagnostic while the clone workup is still open. Grade 2–3 uptake confirms ATTR without biopsy only when SPEP and sFLC are negative, since a coexisting monoclonal protein reopens the AL question.
- Assuming no myeloma means no AL. Most AL patients do not have overt myeloma.
- Assuming renal-only disease. Asymptomatic cardiac amyloid can coexist and determines prognosis, so check cardiac biomarkers even when the presentation is purely nephrotic.
- Pushing ACEi/ARB hard in ATTR cardiac amyloid; they are often poorly tolerated because of restrictive physiology plus autonomic dysfunction.
Treatment by Subtype, and When to Escalate
- AL: treat the underlying plasma cell clone to eliminate the source of amyloidogenic light chains. First-line is Dara-CyBorD (daratumumab plus cyclophosphamide, bortezomib, dexamethasone), regardless of which organ is involved.
- AL, transplant-eligible: autologous stem cell transplant for younger, fit patients without significant cardiac involvement, which gives the best long-term outcomes; consider after induction.
- Cardiac AL is the prognostic driver: median survival 6 months untreated. Elevated troponin plus NT-proBNP means advanced cardiac involvement by Mayo staging and should accelerate, not delay, referral.
- ATTR: tafamidis 80 mg daily. No chemotherapy, there is no clonal cell population to target.
- AA: treat the underlying inflammatory disease (RA, Crohn, FMF with colchicine). Lowering SAA can halt progression and even allow regression of deposits, which is why disease control is the therapy.
- New complete heart block, syncope, or refractory heart failure: cardiology involvement; restrictive physiology limits standard HF therapy.
- Bilateral carpal tunnel syndrome plus HFpEF plus thick walls in an older patient: order the Tc-PYP scan rather than continuing to titrate diuretics.
Key Evidence
- ANDROMEDA, NEJM 2021: adding daratumumab to CyBorD in newly diagnosed AL doubled the hematologic complete response (53% vs 18%) and improved cardiac and renal organ response. Dara-CyBorD is now the first-line standard.
- ATTR-ACT, NEJM 2018: tafamidis reduced all-cause mortality and cardiovascular hospitalization in ATTR cardiomyopathy, making it genuinely disease-modifying rather than supportive.
- Mayo staging using troponin and NT-proBNP is what converts "cardiac involvement" into a prognosis and a treatment intensity, so send both at diagnosis.
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