Amyloidosis Classification
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Direct answer
Amyloid is any extracellular deposit of misfolded protein in a beta-pleated sheet conformation that stains orange-red with Congo red and shows apple-green birefringence under polarised light — the defining fact of the topic. Classification is by precursor protein: AL from immunoglobulin light chains in plasma cell disorders, AA from serum amyloid A driven by chronic inflammation such as tuberculosis, leprosy and rheumatoid arthritis, and ATTR from transthyretin in senile cardiac and hereditary neuropathic disease. Systemic amyloidosis presents with nephrotic-range proteinuria, restrictive cardiomyopathy, hepatosplenomegaly, and in AL the periorbital purpura and macroglossia that clinicians recognise at the door.
What you must remember
- Structure: non-branching fibrils 7.5–10 nanometres wide, beta-pleated sheet, whatever the precursor — hence one stain serves all types.
- AL (primary): light chains, lambda more than kappa, from a plasma cell dyscrasia; kidney, heart, nerves, gut; macroglossia and periorbital ecchymosis; serum or urine electrophoresis may show a paraprotein, or none visible.
- AA (secondary): serum amyloid A from chronic inflammation — tuberculosis, leprosy, rheumatoid arthritis, inflammatory bowel disease, chronic osteomyelitis — historically the commonest systemic form in India; kidneys first, then liver and spleen.
- ATTR: wild-type transthyretin deposits in the hearts and vessels of elderly men; the hereditary Val30Met variant causes familial amyloid polyneuropathy.
- Localised forms: amyloid beta in Alzheimer disease plaques and in Down syndrome (APP on chromosome 21), islet amyloid polypeptide in type 2 diabetes, atrial natriuretic peptide in atria, procalcitonin-derived amyloid in medullary thyroid carcinoma, beta-2 microglobulin in long-term dialysis (joints, carpal tunnel).
- Organ pathology: kidneys are the most common systemic target (nephrotic syndrome, then renal failure); spleen shows sago (follicular) or lardaceous (diffuse) patterns; the heart is firm, rubbery and stiff; the tongue is enlarged and waxy.
- Diagnosis: abdominal fat pad aspiration or rectal biopsy with Congo red; immunohistochemistry or mass spectrometry types the protein — typing decides treatment, so it is not optional.
- Principle: AA can regress when the driving inflammation is controlled; AL needs chemotherapy against the clone; ATTR now has transthyretin stabilisers and silencing therapies.
Worked example: proteinuria in a man treated for leprosy
A 54-year-old man treated for multibacillary leprosy a decade ago presents with periorbital puffiness and leg swelling; urine protein is 6 grams per day with a bland sediment, and serum albumin is low. Nephrotic syndrome in a leprosy patient has two roads — immune complex glomerulonephritis, which is mesangioproliferative and modest, and AA amyloidosis, which is the one that produces heavy proteinuria. The fat pad aspirate taken at the bedside shows apple-green birefringence under polarised light, Congo red confirming amyloid, and immunostaining for serum amyloid A is positive. Management is the management of the driving inflammation — sustained anti-leprotic and anti-inflammatory control — because removing the antigen supply slowly allows the deposits, held in dynamic equilibrium with serum amyloid A, to regress.
Contrast the other bed on the ward: a 60-year-old with macroglossia, orthostatic hypotension and periorbital purpura ("raccoon eyes") after coughing or proctoscopy, whose free lambda light chains are raised. This is AL amyloidosis; the fat pad is again positive, but the immunostain is for lambda, the heart will be involved with a restrictive physiology and a sparkling echocardiographic texture, and the treatment is clone-directed — bortezomib-based regimes borrowed from myeloma, with autologous transplant for selected patients. Same stain, same apple-green colour, completely different diseases: this pairing is the whole teaching point of classification.
Where students slip
The commonest error is stopping at the stain — identifying amyloid and never typing it, which in practice denies the patient the correct treatment, and in theory answers only half the question. Second, the birefringence gets described carelessly: Congo red alone shows salmon pink; the apple-green appears only under polarised light, and writing "green with Congo red" without mentioning polarisation loses the mark. Third, candidates forget that secondary amyloid spares... rather, that organ involvement differs — AA is renal-dominant while AL is the one with cardiac and neural dominance, a distinction that lets a clinical vignette be answered before the biopsy returns.
Frequently asked questions
Which stain confirms amyloid and what is the finding?
Congo red stain with apple-green birefringence under polarised light; all amyloid types share the beta-pleated sheet conformation that produces it.
What is the precursor protein of AA amyloidosis?
Serum amyloid A, an acute-phase reactant; chronic tuberculosis, leprosy, rheumatoid arthritis and inflammatory bowel disease are the classic drivers.
Which amyloid accumulates in Alzheimer disease?
Amyloid beta, derived from amyloid precursor protein on chromosome 21 — the same basis for early Alzheimer pathology in Down syndrome.
Which amyloid complicates long-term haemodialysis?
Beta-2 microglobulin amyloid, depositing in joints and carpal ligaments.
Which biopsy sites diagnose systemic amyloidosis?
Abdominal fat pad aspiration and rectal biopsy are the standard screening biopsies; the tissue is then typed by immunohistochemistry or mass spectrometry.
Which type causes macroglossia and periorbital purpura?
AL amyloidosis, from monoclonal light chains — lambda predominates — usually without a florid myeloma picture.