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

Amyloidosis is a group of rare but serious disorders caused by the extracellular deposition of misfolded protein fibrils — called amyloid — in tissues and organs, disrupting their normal structure and function. The deposited fibrils adopt a characteristic beta-sheet quaternary structure with pathognomonic Congo red birefringence under polarised light. More than 30 different proteins can form amyloid in humans. The most clinically important systemic types are: AL amyloidosis (immunoglobulin light-chain amyloidosis) — the most common form in high-income countries, caused by abnormal plasma cells producing misfolded immunoglobulin light chains — closely related to multiple myeloma; AA amyloidosis — caused by chronic sustained elevation of the acute-phase protein serum amyloid A (SAA) in the setting of chronic inflammatory or infectious diseases; and ATTR amyloidosis — caused by misfolding of transthyretin (TTR) protein, which occurs either in hereditary (hATTR — due to TTR gene mutations, over 130 known variants) or wild-type (wtATTR — formerly called senile amyloidosis, affecting men over 65 without a TTR mutation). Organs commonly affected include the heart (cardiomyopathy and conduction system disease), kidneys (nephrotic syndrome), peripheral and autonomic nervous system (neuropathy), gastrointestinal tract (dysmotility, malabsorption), and liver. The insidious multi-organ presentation frequently leads to diagnostic delays averaging 2-3 years.

AL amyloidosis is caused by a clonal plasma cell dyscrasia — the abnormal plasma cells produce excess immunoglobulin kappa or lambda light chains that misfold and aggregate as amyloid fibrils; it is associated with monoclonal gammopathy (MGUS or myeloma) and most commonly involves the heart (50%), kidneys (70%), and peripheral nerves (20%). AA amyloidosis is driven by sustained elevation of the acute-phase reactant serum amyloid A (SAA, produced by hepatocytes during inflammation) — causes include longstanding rheumatoid arthritis, inflammatory bowel disease (particularly Crohn's), juvenile idiopathic arthritis, tuberculosis, osteomyelitis, bronchiectasis, and periodic fever syndromes (familial Mediterranean fever); kidneys are predominantly affected (proteinuria and renal failure). Hereditary ATTR (hATTR) amyloidosis is caused by autosomal dominant point mutations in the TTR gene — Val30Met (most common worldwide, endemic in Portugal, Sweden, and Japan), Val122Ile (most common in Afro-Caribbean populations, 3-4% prevalence — causes cardiac-predominant amyloid), and over 130 other variants. Wild-type ATTR (wtATTR) — previously called senile cardiac amyloidosis — occurs due to spontaneous TTR misfolding with ageing, affecting predominantly men over 65-70 and causing isolated cardiomyopathy; found in approximately 10-15% of heart failure with preserved ejection fraction (HFpEF) in elderly patients.

Clinical presentation depends on the amyloid type and organs involved, and is frequently non-specific — causing significant diagnostic delay averaging 2-3 years. Cardiac amyloidosis (AL, wtATTR, hATTR): heart failure with preserved ejection fraction (HFpEF) — progressive dyspnoea, orthopnoea, ankle and leg oedema, and fatigue disproportionate to degree of systolic dysfunction; atrial fibrillation, atrioventricular block, and ventricular arrhythmias causing syncope or sudden death; an important diagnostic clue is poor tolerance of previously well-tolerated medications (ACE inhibitors, beta-blockers) due to low blood pressure from amyloid-related cardiac restriction. Renal amyloidosis (AL, AA): heavy proteinuria — foamy urine — and nephrotic syndrome (hypoalbuminaemia, peripheral oedema); progressive renal failure. Peripheral neuropathy (AL, hATTR): length-dependent sensorimotor neuropathy with numbness, tingling, dysaesthesia, and burning pain in the hands and feet; autonomic neuropathy causing postural hypotension (falls, syncope), erectile dysfunction, diarrhoea or constipation, gastroparesis, and anhidrosis. Classic AL amyloidosis signs: macroglossia (enlarged tongue — present in 10-15%), bilateral periorbital purpura ('raccoon eyes' — caused by amyloid deposition in periorbital vessels), carpal tunnel syndrome (often bilateral, preceding diagnosis by years), and shoulder pad sign (amyloid deposits in shoulder joint capsules). Gastrointestinal: diarrhoea, malabsorption, weight loss, nausea, and gastrointestinal bleeding. Hepatomegaly from amyloid infiltration of the liver — causes raised alkaline phosphatase without significant jaundice early on.

Diagnosis of amyloidosis requires confirmation of amyloid deposition and precise typing. Tissue biopsy with Congo red staining showing apple-green birefringence under cross-polarised light is the gold standard. The least invasive first-line biopsy is abdominal subcutaneous fat pad aspiration (sensitivity 60-80% for AL); rectal biopsy (sensitivity ~80%) or minor salivary gland biopsy are alternatives. If these are negative but suspicion remains high, biopsy of the affected organ (renal, cardiac, liver, nerve) is performed. Amyloid typing — critical because treatment is completely different by type — is done by immunohistochemistry (IHC) or, more accurately, by laser capture microdissection and mass spectrometry-based proteomics at specialist amyloid centres. For AL amyloidosis: serum and urine protein electrophoresis (SPEP/UPEP) and immunofixation to detect monoclonal immunoglobulin; serum free light chain (sFLC) assay (kappa/lambda ratio); bone marrow trephine to quantify and phenotype the plasma cell clone. For ATTR: technetium-labelled bisphosphonate (99mTc-PYP or 99mTc-DPD) nuclear scintigraphy shows grade 2-3 cardiac uptake highly specific for ATTR cardiac amyloidosis (Perugini grade 2-3 in the absence of AL is diagnostic without biopsy in 97% of cases); TTR gene sequencing to distinguish hereditary from wild-type. Echocardiography: concentric biventricular wall thickening, preserved or mildly reduced ejection fraction, 'granular sparkling' myocardial texture, bi-atrial dilatation, diastolic dysfunction. Cardiac MRI: diffuse subendocardial or transmural late gadolinium enhancement with abnormal gadolinium kinetics. NT-proBNP, troponin T, and serum amyloid P (SAP) scintigraphy (UK specialist centres) assess organ load and treatment response.

Treatment is highly type-specific and requires management at a specialist amyloid centre. AL amyloidosis: chemotherapy targeting the underlying plasma cell clone — the standard regimen is bortezomib-cyclophosphamide-dexamethasone (VCd or CyBorD); daratumumab (anti-CD38 monoclonal antibody) combined with VCd (daratumumab-VCd, or 'Dara-VCd') is now the preferred first-line combination therapy for transplant-ineligible patients; autologous stem cell transplant (ASCT) for carefully selected eligible patients (cardiac function sufficient, limited organ impairment). The treatment goal is achieving very good partial response (VGPR) or better haematologic response — defined as dFLC (difference between involved and uninvolved free light chains) below 40 mg/L — which allows organ recovery. Supportive therapy: diuretics (loop diuretics, avoiding hypotension); subcutaneous compression for oedema; lactulose and dietary modifications for GI dysmotility. AA amyloidosis: aggressive suppression of the underlying inflammatory disease using DMARDs and biologics (anti-IL-6 for RA, anti-TNF for IBD); colchicine for familial Mediterranean fever dramatically reduces SAA and prevents AA amyloid progression; an anti-SAP antibody (CPHPC + anti-SAP) is in clinical trials. ATTR cardiomyopathy: tafamidis (a TTR tetramer stabiliser — 61 mg/day, oral) significantly reduces all-cause mortality and cardiovascular hospitalisation (ATTR-ACT trial — 30% relative risk reduction); acoramidis (a next-generation stabiliser) shows even greater stabilisation; diflunisal (an NSAID stabiliser — used off-label). ATTR neuropathy: patisiran (RNA interference, IV q3 weeks), vutrisiran (RNAi, SC quarterly), or inotersen (antisense oligonucleotide, SC weekly) all reduce TTR production by 80-95% and significantly slow or halt neuropathy progression. Liver transplantation historically used for hATTR as it removes the source of mutant TTR, but largely superseded by gene silencing therapies. Dialysis or kidney transplant for end-stage renal amyloidosis.

Untreated AL amyloidosis with cardiac involvement carries the worst prognosis — median survival of only 6-18 months from diagnosis before modern therapies; Mayo Clinic stage III-IV cardiac AL (elevated NT-proBNP above 8500 ng/L) historically had median survival of 3-4 months without treatment. Cardiac amyloidosis causes progressive restrictive cardiomyopathy with diastolic heart failure, ventricular wall thickening, severely reduced cardiac output, atrial fibrillation, ventricular arrhythmias, and sudden cardiac death from conduction system involvement (complete heart block, VT). Kidney amyloidosis progresses to nephrotic syndrome, with severe hypoalbuminaemia, oedema, and thrombotic complications from urinary immunoglobulin loss, ultimately reaching end-stage renal failure requiring haemodialysis or kidney transplantation. Peripheral and autonomic neuropathy (particularly in hereditary ATTR Val122Ile, Val30Met) causes progressive disability, orthostatic hypotension, impotence, GI dysmotility, and carpal tunnel syndrome. Gastrointestinal amyloidosis causes pseudo-obstruction, malabsorption, protein-losing enteropathy, and severe malnutrition. Hepatic amyloidosis causes cholestatic jaundice and liver failure. Early diagnosis and type-specific treatment significantly improve survival — modern daratumumab-based regimens for AL achieve haematologic complete response in over 50% and median overall survival exceeding 5 years in eligible patients.

AL and wild-type ATTR amyloidosis are not currently preventable. AA amyloidosis is largely preventable by aggressively treating and suppressing the underlying chronic inflammatory disease — effective sustained control of rheumatoid arthritis (using DMARDs and biologics to reduce SAA to below 10 mg/L), inflammatory bowel disease, or recurrent infectious conditions dramatically reduces amyloid deposition risk and can arrest progression. In familial Mediterranean fever, lifelong colchicine essentially eliminates the risk of AA amyloidosis. Genetic counselling is strongly recommended for all first-degree relatives of patients with hereditary ATTR amyloidosis — proactive genetic testing allows early diagnosis before irreversible organ damage occurs, enabling timely initiation of TTR gene-silencing therapy (patisiran, vutrisiran) or TTR stabiliser (tafamidis) before significant neuropathy or cardiomyopathy develops. For patients with ATTR cardiomyopathy, high clinical suspicion in the appropriate context (elderly men with HFpEF and any of carpal tunnel syndrome, lumbar spinal stenosis, or bilateral CTS) should prompt early echocardiography and 99mTc-PYP scintigraphy — diagnosing wtATTR when cardiac function is still relatively preserved dramatically improves the benefit from tafamidis therapy.

Seek urgent or emergency care for: sudden severe breathlessness or ankle swelling suggesting acute cardiac decompensation; acute kidney failure (rapid decline in urine output, severe oedema); or syncope (blackout) in a patient with known or suspected cardiac amyloidosis. See a haematologist or specialist centre urgently if your GP suspects amyloidosis based on the combination of proteinuria, cardiac thickening on echocardiogram, peripheral neuropathy, and elevated serum immunoglobulins — these four together have very high specificity. Patients with a known diagnosis of multiple myeloma or MGUS should be monitored for amyloidosis. If you have a family history of hereditary ATTR amyloidosis (Val122Ile, Val30Met mutations, or other known variants), proactive genetic testing and cardiac and neurological screening is essential — RNA interference therapies (patisiran, vutrisiran) dramatically improve outcomes when started before irreversible nerve damage occurs.