Key Facts

Amyloidosis encompasses a group of diseases characterised by extracellular deposition of misfolded proteins as insoluble fibrils. Over 30 different proteins can form amyloid. The clinical presentation depends on which organs are affected. Early diagnosis is critical but often delayed.

Epidemiology

• AL amyloidosis: incidence ~3–5 per million/year; median age at diagnosis ~65 years
• AA amyloidosis: declining incidence due to better treatment of inflammatory conditions
• ATTR wild-type (senile cardiac amyloidosis): increasingly recognised in elderly patients with HFpEF (~13% of HFpEF in over-60s)
• Hereditary ATTR: rare, specific mutations (e.g. Val122Ile in 3–4% of African Americans)

Aetiology

• AL: clonal plasma cell or lymphoproliferative disorder producing monoclonal light chains (lambda > kappa)
• AA: chronic inflammation → sustained SAA production → deposition (RA, Crohn's, UC, FMF, chronic infection, IV drug use)
• ATTR hereditary: autosomal dominant mutations in transthyretin gene (>130 mutations known; Val30Met most common)
• ATTR wild-type: age-related misfolding of normal transthyretin — cardiac predominant
• Dialysis-related (Aβ2M): beta-2 microglobulin deposition in long-term dialysis patients

Pathophysiology

• Amyloidogenic proteins misfold into beta-pleated sheet configuration
• Beta-sheets polymerise into insoluble fibrils (7–10 nm diameter)
• Fibrils deposit in extracellular space → tissue architecture disruption → organ dysfunction
• In AL: light chain fibrils are directly cytotoxic to cardiomyocytes (cardiotoxic prefibrillar oligomers)
• Progressive accumulation leads to organ enlargement (liver, spleen, tongue) or restrictive pathology (heart, kidneys)

Cardiac Amyloidosis

• Restrictive cardiomyopathy: exertional dyspnoea, peripheral oedema
• Low-voltage ECG despite increased wall thickness on echo (pathognomonic discordance)
• Heart failure with preserved ejection fraction
• Conduction abnormalities, arrhythmias

Renal Amyloidosis

• Nephrotic syndrome (heavy proteinuria, hypoalbuminaemia, oedema)
• Progressive CKD
• Most common organ involvement in AA amyloidosis

Other Organ Involvement

• Hepatic: hepatomegaly, raised ALP (disproportionate to bilirubin)
• Neurological: peripheral neuropathy (sensorimotor), autonomic neuropathy (postural hypotension, GI dysmotility), carpal tunnel syndrome (bilateral — early feature)
• GI: macroglossia (pathognomonic for AL), dysphagia, malabsorption, GI bleeding
• Soft tissue: periorbital purpura (raccoon eyes — pathognomonic for AL), easy bruising (factor X deficiency)

Red Flags

• Unexplained nephrotic syndrome in older adult
• HFpEF with low-voltage ECG and increased wall thickness
• Bilateral carpal tunnel syndrome
• Macroglossia
• Periorbital purpura
• Unexplained peripheral neuropathy with autonomic features

Bedside

• ECG: low-voltage complexes (limb leads), pseudo-infarct pattern (poor R-wave progression)
• Urinalysis: proteinuria
• Blood pressure: postural drop (autonomic neuropathy)

Bloods

• Serum free light chains (FLC): abnormal kappa:lambda ratio in AL
• Serum protein electrophoresis (SPEP) and immunofixation: paraprotein
• NT-proBNP: cardiac involvement staging (>8,500 pg/mL = stage IIIb — poor prognosis)
• Troponin: elevated in cardiac amyloid (staging)
• SAA (serum amyloid A): elevated in AA amyloidosis
• LFTs: raised ALP (hepatic involvement)
• U&Es, albumin: renal involvement

Imaging

• Echocardiography: increased biventricular wall thickness, diastolic dysfunction, granular sparkling appearance, restrictive filling
• Cardiac MRI: late gadolinium enhancement (diffuse subendocardial pattern), elevated native T1 mapping, elevated ECV
• Tc-99m DPD/PYP scintigraphy: highly sensitive and specific for ATTR cardiac amyloid (Perugini grade 2–3 diagnostic without biopsy)
• SAP scintigraphy: maps whole-body amyloid distribution (National Amyloidosis Centre)

Special Tests

• Tissue biopsy: Congo red staining with apple-green birefringence under cross-polarised light
• Abdominal fat pad aspirate: least invasive screening biopsy (~80% sensitivity in AL)
• Bone marrow biopsy: assess clonal plasma cell burden in AL
• Genetic testing: TTR gene sequencing for hereditary ATTR
• Mass spectrometry: gold standard for amyloid typing on biopsy tissue

Non-pharmacological

• Fluid and salt restriction for cardiac/renal involvement
• Compression stockings for postural hypotension
• Dietary modification: phosphate/potassium restriction if CKD
• National Amyloidosis Centre referral (Royal Free Hospital, London) for all suspected cases

Pharmacological

AL amyloidosis:

• First-line: bortezomib-cyclophosphamide-dexamethasone (VCD/CyBorD)
• Alternative: melphalan-dexamethasone (for transplant-ineligible)
• Daratumumab-VCD (Dara-VCD): ANDROMEDA trial showed improved haematological response
• Autologous stem cell transplant (ASCT): for selected fit patients (cardiac stage I–II, age <70, eGFR >50)

AA amyloidosis:

• Treat underlying inflammatory condition aggressively (reduce SAA to <10 mg/L)
• Anti-IL-1 (anakinra), anti-IL-6 (tocilizumab) for refractory inflammation
• Colchicine 0.5mg BD for FMF-related AA amyloidosis

ATTR amyloidosis:

• Tafamidis 80mg OD (TTR stabiliser) — ATTR-ACT trial showed reduced mortality and CV hospitalisations (NICE TA870 for ATTR cardiomyopathy)
• Patisiran (siRNA) or inotersen (antisense oligonucleotide): for hereditary ATTR with polyneuropathy (NICE HST21, TA803)
• Liver transplantation: curative for hereditary ATTR (liver is main source of TTR)

Supportive:

• Heart failure: diuretics cautiously (low-dose furosemide); avoid beta-blockers, ACEi, digoxin (bind to amyloid fibrils)
• Nephrotic syndrome: diuretics, ACEi for proteinuria
• Neuropathy: gabapentin/pregabalin for neuropathic pain

Surgical/Interventional

• ASCT: in selected AL amyloidosis
• Cardiac transplantation: highly selected cases
• Renal transplantation: if source of amyloid controlled
• Pacemaker/ICD: for conduction disease/arrhythmias

Referral Criteria

• All suspected amyloidosis → National Amyloidosis Centre (Royal Free Hospital)
• Haematology: AL amyloidosis
• Cardiology: cardiac amyloidosis (cardiac MRI, Tc-99m DPD scan)
• Nephrology: renal amyloidosis

• AL amyloidosis: median survival 12–18 months untreated; with VCD/ASCT ~4–5 years; stage IIIb (NT-proBNP >8500) median survival ~6 months
• AA amyloidosis: prognosis depends on underlying disease control; renal failure main cause of death
• ATTR wild-type: median survival ~3.5 years from diagnosis; tafamidis improves survival
• ATTR hereditary (Val30Met): 5–15 year survival; liver transplant/gene silencing improves outcomes
• Cardiac involvement is the major determinant of prognosis across all types
• Haematological complete response in AL: median survival >8 years

Amyloidosis Classification

Mayo Staging for AL Cardiac Amyloidosis