Amyloidosis — Types, Causes, Diagnosis & Treatment Guide — Symptoms, Causes & Treatment | MyMedicPlus

Amyloidosis is a group of diseases characterised by the extracellular deposition of insoluble fibrillar protein aggregates (amyloid fibrils) in organs and tissues. All amyloid fibrils share a common beta-pleated sheet structure that confers resistance to proteolysis, allowing accumulation in tissues — the deposits stain salmon-pink with Congo red dye and display characteristic apple-green birefringence under polarised light, the hallmark histological finding. Over 30 different proteins can misfold and polymerise to form amyloid fibrils — each defining a different amyloidosis type named by the precursor protein (e.g., AL for immunoglobulin light chain, ATTR for transthyretin). The major clinically significant types are: AL (light chain) amyloidosis — plasma cell dyscrasia producing amyloidogenic free light chains; ATTR (transthyretin) amyloidosis — either hereditary (ATTRv — due to TTR gene mutations causing unstable TTR tetramer) or wild-type (ATTRwt — formerly 'senile systemic amyloidosis' — occurring in men over 65 without TTR mutation); and AA (reactive) amyloidosis — from chronic inflammatory conditions causing serum amyloid A protein (SAA) overproduction. Amyloidosis is underdiagnosed — particularly ATTR cardiac amyloidosis, which may affect 10-15% of patients with heart failure with preserved ejection fraction and is increasingly recognised with advances in cardiac imaging and nuclear scintigraphy. Amyloidosis specialist centres (National Amyloidosis Centre, London; Boston University) provide comprehensive multidisciplinary expertise.

AL (immunoglobulin light chain) amyloidosis: the most common type in high-income countries. Caused by a clonal plasma cell disorder (similar pathophysiology to multiple myeloma — but amyloidogenic rather than myeloma-defining M-protein) producing amyloidogenic free light chains (predominantly lambda type) that misfold and deposit. Associated with plasma cell disorders in approximately 10-15%; can occur with B-cell lymphoma. Most common targets: kidneys (nephrotic syndrome), heart (infiltrative cardiomyopathy), peripheral nerves, liver, and GI tract. ATTR (transthyretin) amyloidosis: Transthyretin (TTR) is a tetrameric plasma protein produced by the liver that transports thyroxine and retinol. Wild-type ATTR (ATTRwt): TTR tetramer destabilises with aging → monomer dissociation → misfolding and amyloid fibril formation; predominantly affects the heart (infiltrative cardiomyopathy) and carpal tunnel (carpal tunnel syndrome — often preceding cardiac involvement by 5-10 years); affects predominantly men over 65; increasingly common — estimated prevalence in heart failure with preserved EF is 10-15%. Hereditary ATTR (ATTRv): caused by over 130 pathogenic TTR gene mutations — the most common being Val122Ile (prevalent in 3-4% of African Americans — causes cardiac involvement), Val30Met (most common worldwide — causes peripheral neuropathy predominantly). AA (reactive) amyloidosis: caused by chronic sustained elevation of serum amyloid A (SAA) — an acute phase reactant produced in response to chronic inflammation. Associated with: rheumatoid arthritis; ankylosing spondylitis; inflammatory bowel disease; psoriasis; chronic infections (TB, bronchiectasis, osteomyelitis); and familial Mediterranean fever (FMF). Predominantly affects the kidneys (nephrotic syndrome), liver, and spleen. Other types: Abeta2M (dialysis-related amyloidosis — beta-2-microglobulin accumulation in carpal tunnel in long-term dialysis patients); hereditary lysozyme, fibrinogen, apolipoprotein AI/AII; localised amyloidosis (confined to one organ — most common in the heart as AL or ATTR).

Amyloidosis symptoms depend on which organs are predominantly affected by amyloid deposition. Cardiac amyloidosis (AL or ATTR): heart failure (breathlessness, orthopnoea, ankle oedema, fatigue); atrial fibrillation; heart block; low voltage ECG despite increased echocardiographic wall thickness (characteristic); exertional presyncope or syncope; and chest pain. The diagnosis should be suspected in any patient with 'thick-walled' heart on echo but low voltage on ECG, heart failure with preserved ejection fraction in an elderly man, or bilateral carpal tunnel syndrome preceding heart failure. Renal amyloidosis (AL or AA): nephrotic syndrome (massive proteinuria — foamy urine, hypoalbuminaemia causing oedema — periorbital, peripheral, ascites); progressive renal failure. Peripheral neuropathy (AL or ATTRv): progressive length-dependent sensorimotor neuropathy (starting in the feet — numbness, tingling, burning pain, weakness); autonomic neuropathy (postural hypotension causing falls, diarrhoea or constipation alternating, erectile dysfunction, urinary retention) — autonomic neuropathy is particularly prominent in familial ATTR and can dominate the clinical picture. Hepatic amyloidosis: hepatomegaly, sometimes massive; raised alkaline phosphatase (ALP); jaundice (uncommon). GI amyloidosis: malabsorption, diarrhoea, early satiety, GI bleeding, dysmotility. Macroglossia (enlarged tongue — with scalloped indentations from teeth — the most pathognomonic clinical sign of AL amyloidosis). 'Racoon eyes' (periorbital ecchymosis from AL amyloidosis causing capillary fragility — a rare but highly specific sign). Soft tissue deposits: carpal tunnel syndrome (bilateral — characteristic of ATTR amyloidosis), shoulder pad sign, submandibular gland enlargement.

Diagnosis of amyloidosis requires tissue biopsy with Congo red staining showing apple-green birefringence under polarised light, combined with typing of the amyloid fibril protein to guide appropriate treatment (as management is fundamentally different between AL and ATTR). Abdominal fat pad aspirate: simple outpatient procedure — positive in approximately 80% of AL, 70% of ATTR; avoids more invasive organ biopsy as first step. Bone marrow trephine (if plasma cell dyscrasia suspected): provides amyloid typing and plasma cell clone characterisation. Organ biopsy (kidney, liver, heart, nerve): definitive but invasive — used if fat pad aspirate is negative and high clinical suspicion remains. Amyloid typing: immunohistochemistry (IHC) — antibodies against specific proteins; laser capture microdissection with mass spectrometry (gold standard for typing — performed at specialist centres — identifies amyloid type with high accuracy). Haematological investigations (AL amyloidosis): serum free light chains (FLC) and serum protein electrophoresis with immunofixation — identifies monoclonal light chain; bone marrow biopsy for plasma cell percentage; 24-hour urine electrophoresis. Cardiac investigations: 12-lead ECG (low voltage pattern + left bundle branch block — characteristic of cardiac amyloidosis); echocardiogram (increased left ventricular wall thickness with preserved or reduced EF; 'sparkling' or granular myocardium on echo; diastolic dysfunction; atrial dilatation; pericardial effusion); cardiac MRI with gadolinium (diffuse subendocardial late gadolinium enhancement — 'transmural enhancement' — characteristic amyloid pattern); cardiac biomarkers (NT-proBNP and troponin — highly elevated; form the basis of the Mayo staging system for AL amyloidosis — highest prognostic value). Nuclear scintigraphy (99mTc-DPD, 99mTc-PYP, or 99mTc-HMDP): the most important non-invasive diagnostic advance for ATTR cardiac amyloidosis — grade 2-3 cardiac uptake (equal to or greater than bone) with absent monoclonal protein allows confident diagnosis of ATTR without biopsy in the correct clinical context. Nerve conduction studies and EMG for neuropathy. Renal biopsy (for significant renal involvement). MRI of the spine (cervical/lumbar — spinal canal amyloid deposits).

Treatment is highly amyloidosis-type specific and is best delivered at specialist multidisciplinary amyloidosis centres. AL (light chain) amyloidosis: the goal is to eliminate the amyloidogenic plasma cell clone, halting amyloid production and allowing some organ recovery in responsive patients. Chemotherapy regimens: bortezomib (a proteasome inhibitor) + cyclophosphamide + dexamethasone (VCd or CyBorD) — achieves complete haematological response (CR) in 40-60%; daratumumab (anti-CD38 monoclonal antibody) + VCd (D-VCd/DARA) — approved 2021 — achieves CR in 53% vs 18% with VCd alone; melphalan + dexamethasone (MDex — used in patients ineligible for bortezomib). Autologous stem cell transplantation (ASCT) — peripheral blood stem cells harvested then high-dose melphalan followed by stem cell infusion — achieves CR in 35-40% in carefully selected younger patients with limited organ involvement — provides durable responses. Organ-specific support: diuretics and careful fluid management for cardiac amyloidosis (avoid ACE inhibitors/ARBs if hypotensive — poorly tolerated; avoid digoxin — bound by amyloid and toxic); renal transplantation in AA/AL renal amyloidosis following disease control; heart transplantation in severe cardiac AL amyloidosis (followed immediately by ASCT to prevent graft amyloidosis). ATTR amyloidosis: Tafamidis (Vyndaqel 61mg or Vyndamax 80mg — oral once daily): TTR tetramer stabiliser — slows progression of wild-type and Val122Ile/Val30Met ATTR cardiomyopathy; the ATTR-ACT trial (2018) demonstrated 30% reduction in all-cause mortality and 32% reduction in cardiovascular hospitalisations over 30 months vs placebo in ATTRwt and hereditary ATTR cardiac amyloidosis. Now standard of care for all ATTR cardiac amyloidosis patients. Patisiran (Onpattro — IV siRNA): RNA interference silencing TTR production — first-line for hereditary ATTRv polyneuropathy with cardiac involvement (APOLLO trial — 56% improvement in neuropathy progression vs 4% with placebo). Inotersen (Tegsedi — subcutaneous antisense oligonucleotide): licensed for hereditary ATTRv polyneuropathy. Vutrisiran (subcutaneous siRNA — more convenient than IV patisiran): approved 2022. Eplontersen (subcutaneous ASO) — approved 2023 for ATTRv with polyneuropathy. Acoramidis (ATTRibute-CM trial) — another TTR stabiliser — approved 2024. AA amyloidosis: treat the underlying inflammatory condition — effective suppression of SAA production halts amyloid deposition and allows regression; methotrexate, anti-TNF biologics (for RA), colchicine (for FMF — highly effective); targeted treatment of the underlying infection or inflammation.

Amyloidosis causes severe multi-organ complications depending on type and organs involved. Cardiac complications: amyloid cardiomyopathy causes progressive restrictive diastolic heart failure, exercise intolerance, fluid retention, and low cardiac output; arrhythmias including AF, heart block, and ventricular arrhythmias are common; AL cardiac amyloidosis carries a median survival of 6 months without treatment if the heart is severely involved; sudden cardiac death from arrhythmia is a significant risk. Renal complications: nephrotic syndrome (massive proteinuria causing oedema, hypoalbuminaemia, hyperlipidaemia) progresses to chronic kidney disease and end-stage renal disease requiring dialysis in AL and AA amyloidosis. Peripheral and autonomic neuropathy: severe burning neuropathic pain, postural hypotension, gastroparesis, diarrhoea, bladder dysfunction, and impotence severely impair quality of life in ATTRv polyneuropathy and AL amyloidosis. Gastrointestinal complications: macroglossia (pathognomonic for AL amyloidosis) causes dysphagia and obstructive sleep apnoea; GI infiltration causes malabsorption and protein-losing enteropathy. Periorbital ecchymosis ('raccoon eyes' — spontaneous periorbital bleeding from amyloid infiltration of periorbital blood vessels) is highly specific for AL amyloidosis. Coagulopathy: Factor X deficiency (adsorbed onto amyloid fibrils) in AL amyloidosis causes a significant bleeding diathesis. ATTR cardiomyopathy complications: bilateral carpal tunnel syndrome (often precedes cardiac symptoms by 5–10 years); lumbar spinal stenosis; biceps tendon rupture; progressive heart failure and sudden cardiac death. Treatment complications: ASCT for AL amyloidosis carries approximately 1–5% treatment-related mortality; bortezomib causes peripheral neuropathy in a dose-dependent fashion.

AL amyloidosis: there is no primary prevention as the plasma cell clone arises from random somatic mutations. Regular monitoring of MGUS (monoclonal gammopathy of undetermined significance) — a precursor state — allows early detection of progression to AL amyloidosis or myeloma; annual haematology review is recommended for MGUS patients. ATTR amyloidosis: hereditary ATTR (ATTRv) is autosomal dominant — genetic counselling for all first-degree relatives of confirmed ATTRv gene carriers is essential; presymptomatic genetic testing identifies carriers before organ damage; early treatment with TTR-silencing agents (patisiran, inotersen) or stabilisers can be initiated before significant organ damage develops. Carpal tunnel syndrome (bilateral) in a man over 60 is a strong signal to investigate for ATTR amyloidosis with nuclear scintigraphy and ECG before cardiac involvement becomes severe. AA amyloidosis prevention: effective treatment of underlying chronic inflammatory diseases (RA, IBD, FMF, chronic infections) prevents AA amyloidosis. Colchicine is universally recommended for patients with familial Mediterranean fever (FMF) as it prevents both FMF attacks and AA amyloidosis.

Seek urgent medical attention for: rapidly progressive heart failure in an older man who has had bilateral carpal tunnel surgery (often 5-10 years before cardiac involvement — may indicate ATTR amyloidosis); nephrotic syndrome (massive leg and facial swelling with foamy urine) — urgent nephrology referral; peripheral neuropathy that is progressive, symmetric, and predominantly sensory with autonomic features (postural dizziness, diarrhoea, impotence, bladder dysfunction) — possible ATTRv or AL amyloid neuropathy; and macroglossia (enlarged tongue with tooth marks) — highly suspicious for AL amyloidosis requiring immediate haematology referral. Refer to a specialist (haematology, cardiology, or amyloidosis specialist centre) for: unexplained proteinuria and renal impairment in a patient with a chronic inflammatory condition (AA amyloidosis); biventricular thickening on echocardiogram with diastolic dysfunction in a patient over 60 (possible ATTR); a patient with multiple myeloma developing heart failure or nephrotic syndrome (AL amyloidosis); and any patient with suspected amyloidosis for proper typing before treatment — treating AL amyloidosis as ATTR or vice versa is dangerous. Refer to clinical genetics for: any patient with confirmed hereditary ATTR amyloidosis for family counselling and presymptomatic testing of relatives.