Amyloidosis is a group of diseases in which abnormal proteins called amyloid fibrils accumulate in organs and tissues, disrupting their normal function. The defining characteristic: amyloid fibrils have a characteristic beta-sheet structure that stains red with Congo red dye and shows "apple-green birefringence" under polarised light microscopy. There are many forms of amyloidosis, named by the protein forming the fibrils: AL amyloidosis (immunoglobulin light chains — plasma cell dyscrasia); ATTR amyloidosis (transthyretin — a transport protein made by the liver); AA amyloidosis (serum amyloid A — from chronic inflammation). The heart, kidneys, liver, peripheral nerves and soft tissues are the most commonly affected organs.

What is the difference between AL and ATTR amyloidosis?

These are the two most clinically important forms: AL (light chain) amyloidosis: caused by abnormal plasma cells (as in multiple myeloma or MGUS) producing excess immunoglobulin light chains that misfold into amyloid. Pathognomonic signs: macroglossia (enlarged tongue — seen in ~15%); periorbital purpura. Multi-organ: heart (most lethal), kidneys, liver, nerves. Treated with anti-myeloma drugs (daratumumab, bortezomib). ATTR (transthyretin) amyloidosis: caused by the liver's transthyretin protein depositing in the heart (and nerves). Two forms: ATTRv (genetic TTR mutations — hereditary); ATTRwt (wild-type, no mutation — age-related, primarily cardiac). Treated with tafamidis. Distinguishing them is essential before starting treatment.

Why is ATTR cardiomyopathy a "hidden epidemic"?

Wild-type ATTR cardiomyopathy (ATTRwt) accumulates gradually in the hearts of older men over decades, masquerading as "hypertensive heart disease" or "heart failure with preserved ejection fraction (HFpEF)." Studies have shown that approximately 13% of HFpEF patients and 16% of patients with severe aortic stenosis having TAVI procedures have unsuspected ATTR amyloid deposits in their hearts. Most have never been diagnosed — because the diagnostic clues (low ECG voltages despite increased wall thickness on echo; carpal tunnel syndrome preceding heart failure by years; biceps tendon rupture; spinal stenosis) are not systematically screened for. With tafamidis now approved and effective, the urgency of diagnosis is high: earlier treatment prevents more damage.

How is ATTR cardiomyopathy diagnosed?

The modern diagnostic algorithm: (1) Suspect: patient with HFpEF + increased LV wall thickness on echo + characteristic features (low ECG voltages; carpal tunnel syndrome years before cardiac symptoms; biceps tendon rupture; bilateral carpal tunnel; ECG-echo discordance). (2) Exclude AL: serum free light chains (kappa and lambda) + SPEP + UPEP + IF electrophoresis — must be negative before diagnosing ATTR. (3) Bone scintigraphy: DPD/PYP/HMDP scan — grade 2-3 cardiac uptake with negative light chains = non-invasive ATTR diagnosis (no biopsy needed). (4) Genetic testing: TTR gene sequencing to determine ATTRwt vs ATTRv. (5) Start tafamidis as early as possible.

How effective is tafamidis?

ATTR-ACT (NEJM 2018): the pivotal tafamidis trial in ATTR cardiomyopathy. 441 patients (both ATTRwt and ATTRv) randomised to tafamidis 80mg, 20mg or placebo for 30 months. Results (tafamidis 80mg vs placebo): All-cause mortality: 29.5% relative risk reduction (absolute risk reduction approximately 10% at 30 months). CV hospitalisation: 32% reduction. Functional capacity (6MWD, KCCQ score): significantly better preserved with tafamidis. Tafamidis is NOT a cure — it stabilises TTR and prevents new amyloid deposition but does not dissolve existing amyloid. Patients started earlier (better functional class) derive greater benefit. The drug is expensive (~$225,000/year in the USA) — access and cost-effectiveness remain significant issues.

How does GMJ News cover amyloidosis?

GMJ News covers tafamidis ATTR-ACT trial (first approved treatment), the ATTRwt hidden epidemic in HFpEF (13%), the ECG-echo discordance, bone scintigraphy diagnosis, AL vs ATTR distinction (mandatory before treating), Val122Ile variant in Black populations (equity), patisiran RNA interference, AL daratumumab treatment, periorbital purpura and macroglossia as AL clues, and the RNA silencing therapies for ATTRv polyneuropathy. Amyloidosis is directly relevant to PHIG's cardiology programme and Georgia's rare disease identification capacity.

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Amyloidosis

GMJ News knowledge hub · last reviewed September 2026 · Georgian Medical Journal

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Amyloidosis — defined by extracellular deposition of misfolded protein fibrils that disrupt organ architecture and function — encompasses two major clinical forms relevant to modern medicine: AL (immunoglobulin light chain) amyloidosis, driven by plasma cell dyscrasia and causing multi-organ failure (heart, kidneys, liver, nerves); and ATTR (transthyretin) cardiomyopathy, caused by TTR protein deposits in the heart — previously thought rare but now recognised as an extremely common and underdiagnosed cause of heart failure with preserved ejection fraction (HFpEF) in elderly men, estimated to affect approximately 13% of HFpEF patients and 16% of patients with severe aortic stenosis undergoing TAVI (WHO). Tafamidis (Vyndamax/Vyndaqel, Pfizer) — FDA approved May 2019 — is the game-changing first approved treatment for ATTR cardiomyopathy: reducing all-cause mortality by 29.5% and cardiovascular hospitalisation by 32% in the ATTR-ACT trial (NEJM 2018).

Key messages

Tafamidis — first approved ATTR cardiomyopathy treatment (FDA 2019)

Tafamidis (Vyndamax/Vyndaqel, Pfizer) — a TTR tetramer stabiliser — FDA-approved May 2019 for ATTR cardiomyopathy (both hereditary ATTRv and wild-type ATTRwt). ATTR-ACT trial (NEJM 2018): tafamidis 80mg vs placebo over 30 months: 29.5% reduction in all-cause mortality (HR 0.70); 32% reduction in cardiovascular hospitalisation. The first disease-modifying treatment for what was previously considered an untreatable condition.

Wild-type ATTR — the hidden epidemic in HFpEF

Wild-type ATTR cardiomyopathy (ATTRwt — formerly "senile cardiac amyloidosis") occurs when normal TTR protein deposits in the heart of older men (predominantly >75 years) without any genetic mutation. It is dramatically underdiagnosed: approximately 13% of HFpEF patients and approximately 16% of patients undergoing TAVI for severe aortic stenosis have ATTRwt — yet most go undiagnosed. The "low-voltage, thick wall" ECG-echo discordance should trigger diagnostic workup.

Bone scintigraphy — the non-invasive ATTR diagnosis

DPD, PYP or HMDP bone scintigraphy (radiopharmaceuticals that bind ATTR amyloid in cardiac tissue) — when grade 2 or 3 cardiac uptake is detected AND serum free light chains and SPEP/UPEP are negative — provides a non-invasive diagnosis of ATTR cardiomyopathy without biopsy. This has revolutionised diagnosis — previously requiring myocardial biopsy.

AL vs ATTR — the critical diagnostic distinction

AL (light chain) amyloidosis and ATTR amyloidosis both cause cardiac amyloidosis but have completely different causes, prognoses and treatments. Confusing them has lethal consequences: tafamidis treats ATTR; anti-myeloma therapy (daratumumab, bortezomib, lenalidomide) treats AL. Before diagnosing ATTR cardiac amyloidosis, AL MUST be excluded with serum free light chains + SPEP + UPEP + bone marrow biopsy.

The "low-voltage thick wall" ECG-echo mismatch — the diagnostic clue

A patient with significantly increased ventricular wall thickness on echocardiography but low ECG voltages (QRS amplitude is low or normal despite the thick walls) represents the classical ECG-echocardiographic discordance of cardiac amyloidosis. In typical LVH (from hypertension, AS), increased wall thickness → high ECG voltages. In amyloid: the amyloid deposits electrically insulate the myocardium → low voltages despite "pseudo-LVH". This ECG-echo mismatch should immediately trigger amyloidosis workup.

RNA silencing therapies — curative potential for ATTRv polyneuropathy

For hereditary ATTR polyneuropathy (ATTRv — nerve damage from amyloid deposits): Patisiran (Onpattro, Alnylam) — siRNA IV infusion — FDA 2018: first RNA interference drug approved; reduces TTR mRNA production by approximately 80%; stops disease progression and may improve neuropathy. Inotersen (Tegsedi) — antisense oligonucleotide SC — FDA 2018. Vutrisiran (Amvuttra) — next-gen siRNA (monthly SC) — FDA 2022; improved convenience. These drugs prevent new TTR production — potentially stopping the underlying disease.

Key statistics

May 2019

tafamidis FDA approval for ATTR cardiomyopathy — first disease-modifying treatment

FDA 2019

29.5%

reduction in all-cause mortality with tafamidis (ATTR-ACT trial, NEJM 2018)

NEJM 2018

~13%

of HFpEF patients have wild-type ATTR cardiomyopathy (most undiagnosed)

NEJM/Cardiology

~16%

of severe aortic stenosis patients undergoing TAVI have ATTR amyloid

JACC 2020

Val122Ile

TTR variant causing ATTR cardiomyopathy; prevalence ~3-4% in Black/African American population

Genetics

Grade 2-3

bone scintigraphy uptake + negative light chains = non-invasive ATTR diagnosis (no biopsy needed)

ESC/Cardiology

Cardiac amyloidosis — diagnostic algorithm (ECG-echo discordance to treatment)

Source: ESC 2023. The sequence: suspect → exclude AL → bone scan → diagnose ATTR → tafamidis.

Glossary of key terms

Transthyretin (TTR)
BiochemistryA tetrameric transport protein synthesised predominantly by the liver — transports thyroxine (T4) and retinol-binding protein. In amyloidosis, TTR monomers misfold and aggregate into amyloid fibrils — depositing in the heart (cardiomyopathy), peripheral nerves (polyneuropathy), and other organs. Two forms: ATTRv (variant) — germline TTR mutations cause conformationally unstable TTR that misfolds more easily; ATTRwt (wild-type) — normal TTR deposits in the elderly, particularly in the heart, without any mutation. Tafamidis stabilises the TTR tetramer, preventing monomer dissociation and amyloid fibril formation.

AL (light chain) amyloidosis
Haematology/CardiologyThe most common amyloidosis in HICs. Caused by plasma cell dyscrasia (typically MGUS or smouldering/overt multiple myeloma) producing excess immunoglobulin free light chains (kappa or lambda) that misfold into amyloid fibrils. Multi-organ: heart (the most lethal site — HFpEF, rapid decline), kidneys (proteinuria → nephrotic syndrome), liver (enlarged, splenomegaly), peripheral nerves, tongue (macroglossia — pathognomonic), skin (periorbital purpura — pathognomonic). Prognosis before treatment: median survival 18 months for cardiac AL. Treatment: anti-plasma cell therapy (daratumumab + bortezomib + cyclophosphamide + dexamethasone — ANDROMEDA trial: significantly improved outcomes); autologous SCT in eligible patients.

Tafamidis (Vyndamax/Vyndaqel)
FDA 2019/PfizerA small molecule benzoxazole that binds to the thyroxine-binding sites of the TTR tetramer — stabilising the native tetrameric structure and preventing monomer dissociation → no misfold → no amyloid fibril formation. Two formulations: Vyndaqel (tafamidis meglumine 80mg); Vyndamax (tafamidis free acid 61mg — equivalent dosing). ATTR-ACT trial: placebo-controlled, 3 arms (80mg, 20mg, placebo), 441 patients, 30 months. Result: 80mg reduced all-cause mortality 29.5%, CV hospitalisation 32%. The drug does not dissolve existing amyloid — it prevents new deposition. Earlier treatment → better outcomes (critical for early diagnosis).

Patisiran (Onpattro) — RNA interference
FDA 2018/AlnylamThe first RNA interference (RNAi) drug approved by FDA (August 2018) — for hereditary ATTR polyneuropathy. Patisiran is a lipid nanoparticle-encapsulated siRNA targeting TTR mRNA — reducing hepatic TTR production by approximately 80%. Mechanism: siRNA binds to complementary TTR mRNA sequence → mRNA cleavage by the RISC complex → reduced TTR protein production → fewer amyloid fibrils. APOLLO trial (NEJM 2018): significant improvement in neuropathy scores vs placebo; also showed reduction in cardiac amyloid by scintigraphy. Given IV every 3 weeks.

Bone scintigraphy (DPD/PYP/HMDP)
Nuclear medicineRadiolabelled bisphosphonate compounds — originally developed for bone imaging — have been found to preferentially accumulate in ATTR cardiac amyloid (not AL). The three agents used: DPD (3,3-diphosphono-1,2-propanodicarboxylic acid — most common in Europe); PYP (pyrophosphate — most common in USA); HMDP (hydroxymethylene diphosphonate). Grading: Grade 0 (no cardiac uptake); Grade 1 (mild, less than bone); Grade 2 (equal to bone); Grade 3 (greater than bone). Grade 2-3 cardiac uptake + negative serum free light chains = non-invasive ATTR diagnosis (specificity >99%). Negative light chains are essential: AL amyloid occasionally gives false-positive bone scintigraphy uptake — missing AL and treating with tafamidis (which doesn't work for AL) would be a serious error.

Val122Ile — common ATTR variant in Black population
Genetics/EquityThe TTR Val122Ile (also called p.Val142Ile) variant is present in approximately 3-4% of self-reported Black or African American individuals — making it one of the most common genetic variants predisposing to cardiovascular disease in this population. Carriers have approximately 3-5× higher risk of heart failure. ATTRv caused by Val122Ile predominantly causes cardiomyopathy (rather than polyneuropathy). Historically massively underdiagnosed — the Val122Ile variant is now recommended for consideration in the diagnostic workup of HFpEF in Black patients, particularly older men. This is a major health equity issue in cardiology.

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Amyloidosis

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