Amyloidosis Study Guide

📖 Core Concepts Amyloidosis – diseases where mis‑folded proteins aggregate extracellularly into β‑sheet fibrils (amyloid) that deposit in tissues. Amyloid Types – designated “A” + precursor protein (e.g., AL = light‑chain, AA = serum amyloid A, ATTR = transthyretin, Aβ2M = β‑2‑microglobulin). Systemic vs. Organ‑Specific – systemic involves ≥2 organ systems; organ‑specific (localized) affects a single tissue. Pathogenesis – mutant or over‑produced precursor protein becomes unstable, dissociates (often tetramer → monomer), mis‑folds, oligomerizes, then forms insoluble fibrils resistant to proteolysis. Key Biomarkers for AL Staging – N‑terminal pro‑brain‑type natriuretic peptide (NT‑proBNP) and cardiac troponin; higher levels → higher stage, worse survival. Diagnostic Hallmark – Congo red staining of tissue shows apple‑green birefringence under polarized light. --- 📌 Must Remember Prevalence – systemic amyloidosis ≈ 30/100 000. Organ Tropism AL: heart, kidneys, peripheral nerves, tongue, shoulders. AA: kidneys (nephrotic syndrome), liver; spares heart. ATTR: peripheral nerves (polyneuropathy) & heart (restrictive cardiomyopathy). Typical AL Cardiac Findings – low voltage ECG, restrictive filling on echo, diastolic + systolic failure. Typical AL Neurologic Signs – macro‑glossia, periorbital purpura, “shoulder‑pad” sign. Staging (AL) – Stage I: NT‑proBNP ≤ 332 pg/mL & troponin ≤ 0.035 ng/mL → median survival  91 mo; Stage III (both high) →  7 mo. First‑line Biopsy – subcutaneous abdominal fat (fat‑pad). Most Reliable Typing – laser microdissection + mass spectrometry. Key Therapies AL (eligible): high‑dose melphalan + autologous stem‑cell transplant. AL (ineligible): Dara‑CyBorD (cyclophosphamide‑bortezomib‑dexamethasone‑daratumumab). AA: treat underlying inflammatory disease. ATTR: tafamidis, diflunisal, inotersen, patisiran, vutrisiran; liver transplant for hereditary forms. Aβ2M: high‑flux dialysis or kidney transplant. --- 🔄 Key Processes Amyloid Formation Mutant/over‑produced protein → tetramer destabilization → monomer release → mis‑folding → oligomer → β‑sheet fibril → extracellular deposition. Diagnostic Workflow Step 1: Clinical suspicion (organ signs, systemic symptoms). Step 2: Fat‑pad biopsy → Congo red → apple‑green birefringence. If negative: Biopsy rectal mucosa, salivary gland, lip, or bone marrow. Step 3: Amyloid typing Serum/urine electrophoresis + immunofixation (detect light chains). Immunohistochemistry (good for AA, less for AL). Laser microdissection + mass spectrometry (gold standard). Step 4: Staging (AL) with NT‑proBNP & troponin. Staging AL (Biomarker‑Based) Assign 1 point for NT‑proBNP > 332 pg/mL. Assign 1 point for troponin > 0.035 ng/mL. Total 0 → Stage I, 1 → Stage II, 2 → Stage III. Treatment Decision Tree Is the amyloid AL? → assess transplant eligibility → transplant vs. Dara‑CyBorD. Is it AA? → control chronic inflammation. Is it ATTR? → determine wild‑type vs. hereditary → tafamidis ± RNA‑targeted therapy vs. liver transplant. --- 🔍 Key Comparisons AL vs. AA Cardiac Involvement AL: frequent, low‑voltage ECG, restrictive diastolic pattern, may have systolic dysfunction. AA: usually spares the heart. Light‑Chain vs. Transthyretin Amyloidosis (Organ Preference) Light‑Chain (AL): heart, kidneys, tongue, shoulder pads. ATTR: peripheral nerves (polyneuropathy) & heart (restrictive cardiomyopathy). Biopsy Site Sensitivity Fat‑pad: easy, first line, 85 % diagnostic yield when positive. Rectal / Salivary / Lip / Bone Marrow: used if fat‑pad negative; together raise overall yield to 85 %. Amyloid Typing Accuracy Immunohistochemistry: good for AA, often misses AL. Mass Spectrometry: most reliable for all types. --- ⚠️ Common Misunderstandings “All amyloidosis has cardiac involvement.” – Only AL and ATTR commonly affect the heart; AA usually does not. “A negative fat‑pad biopsy rules out amyloidosis.” – False‑negatives occur; proceed to alternative sites if suspicion remains high. “Tafamidis works for any amyloid type.” – It stabilizes transthyretin only (ATTR); ineffective for AL or AA. “High‑dose melphalan transplant is suitable for everyone with AL.” – Only 20‑25 % meet eligibility criteria (organ function, performance status). --- 🧠 Mental Models / Intuition “Protein stability → organ risk” – The less stable the precursor (mutant tetramer → monomers), the more likely it will form amyloid in tissues where that protein circulates (e.g., transthyretin → nerves & heart). “Birefringence = amyloid” – Imagine a polarized light microscope as a “secret decoder” that only reveals the green glow when amyloid is present. “Stage = biomarker count” – Think of AL staging like a simple 0‑2 point game; each high biomarker adds a point, and the total predicts survival. --- 🚩 Exceptions & Edge Cases Hereditary vs. Wild‑type ATTR – Both present with neuropathy/cardiac disease, but wild‑type occurs only in older adults and lacks a TTR mutation. AL in the Heart without Classic ECG Changes – Some patients may have normal voltage; rely on imaging (echo, nuclear scans) and biopsy. AA with Cardiac Involvement – Rare, but possible in advanced chronic inflammation; do not assume heart is always spared. --- 📍 When to Use Which Biopsy Site Choice – Start with fat‑pad for ease; switch to rectal, salivary, lip, or bone marrow if negative and clinical suspicion persists. Typing Method – Use serum/urine immunofixation first for AL suspicion; follow with mass spectrometry when immunohistochemistry is inconclusive. Therapy Selection AL, transplant‑eligible → high‑dose melphalan + ASCT. AL, transplant‑ineligible → Dara‑CyBorD. ATTR, early disease → tafamidis (stabilizer) ± RNA‑targeted therapy if rapid progression. Hereditary ATTR with organ damage → consider liver transplant if patient is a good surgical candidate. --- 👀 Patterns to Recognize Macroglossia + Periorbital Purpura → AL (high‑yield clue). Nephrotic syndrome + AA serum amyloid A elevation → AA (secondary to chronic inflammation). Length‑dependent sensory loss + autonomic dysfunction (orthostatic hypotension) → hereditary ATTR polyneuropathy. Low‑voltage ECG + restrictive echo + positive fat‑pad biopsy → cardiac AL. --- 🗂️ Exam Traps Distractor: “Tafamidis is approved for AL amyloidosis.” – Wrong; it only stabilizes transthyretin. Distractor: “All systemic amyloidosis presents with macroglossia.” – Only 20 % of AL patients have it; AA and ATTR do not. Distractor: “A negative Congo red stain excludes amyloid.” – False; early deposits or sampling error can give false‑negatives. Distractor: “Serum transthyretin level is elevated in ATTR.” – Level is typically normal; disease is due to mutant protein, not overproduction. Distractor: “High‑dose melphalan is first‑line for every AL patient.” – Only a minority are transplant‑eligible; most receive Dara‑CyBorD. ---