ImmunologyTier 1Medical Sciences concept

Amyloidosis - types and typical organ involvement (AA, AL, ATTR)

Core concept

A misfolded soluble precursor protein polymerises into insoluble beta-pleated sheet fibrils that deposit extracellularly
- The precursor names the type; the type dictates the treatment - typing is the whole diagnostic problem
- All types share Congo red staining with apple-green birefringence under cross-polarised light, and all contain serum amyloid P component
Amyloid is mechanically and functionally disruptive - it causes stiffness, not inflammation

Type	Precursor	Source	Classic organs
AL	Monoclonal immunoglobulin LIGHT CHAIN (lambda > kappa)	Plasma cell dyscrasia	Heart + kidney; also autonomic and peripheral nerve, liver, GI, soft tissue
AA	Serum amyloid A (an acute-phase reactant)	Chronic inflammation - RA, JIA, IBD, FMF and autoinflammatory syndromes, bronchiectasis, chronic infection, IVDU skin sepsis	KIDNEY predominantly (proteinuria), then liver, GI, spleen; heart late and uncommon
ATTRwt (senile/wild-type)	Transthyretin, normal sequence	Age	Heart; bilateral carpal tunnel and lumbar spinal stenosis often precede by years; biceps tendon rupture
ATTRv (hereditary)	Mutant transthyretin - >130 variants; Val30Met commonest (also Val122Ile in ~3-4% of West African ancestry, Thr60Ala Irish)	AD, liver-produced	Val30Met -> familial amyloid POLYNEUROPATHY +/- heart; Val122Ile -> cardiomyopathy
Abeta2M	Beta-2 microglobulin	Long-term dialysis	Carpal tunnel, shoulder, cystic bone
ALECT2	Leukocyte chemotactic factor 2	-	Kidney (Hispanic ancestry)
AApoAI/AFib	Apolipoprotein A-I, fibrinogen alpha	Hereditary	Kidney, liver
Localised (AL, ACal, IAPP)	-	-	Bladder, airway, skin, thyroid (medullary Ca), islets

Key detail

When to suspect

Nephrotic-range proteinuria + heart failure
Thick-walled ventricle with a LOW-VOLTAGE or normal-voltage ECG - the voltage-mass mismatch is the single best clue; hypertrophy on echo should raise voltage, not lower it
Recurrent or bilateral carpal tunnel syndrome in an older patient, especially with heart failure or spinal stenosis
Peripheral and autonomic neuropathy (orthostatic hypotension, gastroparesis, diarrhoea/constipation, erectile dysfunction, bladder dysfunction)
Macroglossia and periorbital purpura are pathognomonic - but only for AL, and present in <20%
Hepatomegaly with inc ALP out of proportion, malabsorption, GI bleeding, factor X deficiency with bleeding (AL only)
"HFpEF" that is intolerant of beta-blockers and ACE inhibitors, with persistently raised troponin and NT-proBNP

Diagnosis - a two-step problem

1. Prove amyloid - Congo red with apple-green birefringence
- Abdominal fat pad aspirate (sens ~70-80% in AL, lower in ATTR), rectal or labial salivary gland biopsy, or the affected organ
- Endomyocardial biopsy is ~100% sensitive when the heart is involved
2. Type it - never assume
- Mass spectrometry on the tissue is the gold standard; immunohistochemistry is unreliable for AL
- Serum/urine electrophoresis + immunofixation + serum free light chain ratio - abnormal in >98% of AL
- 99mTc-DPD/PYP/HMDP bone scintigraphy: Perugini grade 2-3 uptake with NO monoclonal protein = ATTR, diagnostic without biopsy
  - *A monoclonal gammopathy is present in ~40% of elderly people - so a paraprotein plus positive bone scan requires biopsy, not an assumption*
- Genotype TTR in every confirmed ATTR to separate wild-type from hereditary (family implications)
Staging: Mayo AL stage by troponin, NT-proBNP and dFLC; ATTR by NT-proBNP and eGFR

Clinical relevance

Treatment - reduce the precursor, and for ATTR also stabilise it

AL - treat the plasma cell clone
- Daratumumab + bortezomib/cyclophosphamide/dexamethasone (Dara-CyBorD) is standard first-line (ANDROMEDA)
- Autologous stem cell transplant in selected fit patients
- Response is measured by haematological response (dFLC), with organ response lagging by months
- Cardiac AL has the worst prognosis of any amyloidosis - median survival <6 months untreated with advanced cardiac stage
AA - suppress the inflammation
- Treat the driver: colchicine (or IL-1 blockade) for FMF, TNF or IL-6 inhibition for RA/JIA, antimicrobials for chronic infection, surgery for bronchiectasis/osteomyelitis
- Serum amyloid A concentration guides adequacy of suppression - regression of deposits occurs if SAA is normalised
ATTR - stabilise or silence
- Stabilisers: tafamidis (ATTR-CM and ATTRv-PN), acoramidis (ATTR-CM); diflunisal off-label
- Silencers: vutrisiran (siRNA; ATTR-CM and ATTRv-PN), patisiran and eplontersen (ATTRv-PN)
- Nexiguran ziclumeran (nex-z) - in-vivo CRISPR-Cas9 knockout of hepatic TTR, a potential one-off treatment; phase 3, not yet approved
- Liver transplant is largely historical for ATTRv
Supportive: diuretics for congestion; *avoid digoxin, verapamil and diltiazem (bind amyloid fibrils -> toxicity); beta-blockers and ACE inhibitors are poorly tolerated because cardiac output is stroke-volume-limited and rate-dependent*
Anticoagulate AF in cardiac amyloid regardless of CHA2DS2-VASc - atrial mechanical failure gives a high stroke risk

Correlations

Multiple myeloma, MGUS and plasma cell dyscrasias
Restrictive cardiomyopathy and HFpEF
Nephrotic syndrome
Peripheral and autonomic neuropathy
Familial Mediterranean fever and autoinflammatory syndromes
Rheumatoid arthritis complications
Carpal tunnel syndrome and lumbar spinal stenosis

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