Step 1 · General Pathology

Amyloidosis

Name: Amyloidosis
Creator: Veli Bakalov, MD

One misfolded beta-pleated protein, many diseases, one apple-green stain

General Pathology·Systemic·4 min read·9 high-yield points·Reviewed by Veli Bakalov, MD @HemeOncBuddy

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All amyloid is extracellular misfolded protein in β-pleated sheets; Congo red gives apple-green birefringence under polarized light.
AL (primary) amyloid = immunoglobulin light chains (often λ) from myeloma/MGUS; the most common systemic type in developed countries.
AA (secondary) amyloid = serum amyloid A, an acute-phase reactant raised by RA, IBD, chronic infections (TB, osteomyelitis, bronchiectasis), and familial Mediterranean fever; kidney is the main target.
Dialysis-related amyloid = β2-microglobulin (MHC class I light chain) → bilateral carpal tunnel syndrome and destructive arthropathy.
ATTR = transthyretin: hereditary (e.g., V122I in ~4% of Black Americans; cardiomyopathy and/or polyneuropathy) or wild-type senile cardiac amyloid in older men.
Aβ from APP (chromosome 21) forms Alzheimer plaques and cerebral amyloid angiopathy (lobar hemorrhage in the elderly); localized types also include amylin (type 2 diabetes islets), calcitonin (medullary thyroid carcinoma), and ANP (atria).
Cardiac amyloid = restrictive cardiomyopathy with diastolic heart failure: thick walls on echo but low voltage on ECG.
Kidney is the most commonly involved organ: nephrotic-range proteinuria in a patient with a plasma cell disorder or chronic inflammation suggests amyloid.
Macroglossia, periorbital purpura, and acquired factor X deficiency point to AL; diagnose by fat-pad biopsy and type the precursor before treating the source.

What amyloid is

A misfolded protein in β-pleated sheets. Amyloid is an extracellular deposit of misfolded protein arranged in an insoluble β-pleated sheet configuration that resists degradation. Many unrelated precursor proteins can take this shape, which is why one stain unites plasma cell tumors, chronic inflammation, dialysis, and Alzheimer disease. The deposits compress and replace normal tissue, disrupting architecture and organ function.

Appearance. On H&E, amyloid is amorphous, eosinophilic, extracellular hyaline material. Electron microscopy shows rigid, nonbranching fibrils, and every deposit also contains serum amyloid P component regardless of type.

Apple-greenCongo red birefringence under polarized light: the pathognomonic finding for all amyloid

Systemic vs localized. Systemic amyloid circulates as a precursor and deposits in many organs; localized amyloid forms in a single organ from a locally made protein. Boards test the precursor protein behind each type.

Systemic amyloid: the precursor proteins

AL (primary) amyloidosis. Fibrils are immunoglobulin light chains, most often lambda, from a clonal plasma cell dyscrasia such as multiple myeloma or MGUS. It is the most common systemic amyloidosis in developed countries and deposits in heart, kidney, tongue, and nerves.

Clonal plasma cellsMyeloma or MGUS
Excess free light chainsOften lambda
Misfolding into β-sheet fibrilsInsoluble, degradation-resistant
DepositionHeart, kidney, tongue, nerves → organ failure

AL amyloid pathogenesis

AA (secondary) amyloidosis. Fibrils are serum amyloid A (SAA), an acute-phase reactant made by the liver in response to inflammatory cytokines. Chronic inflammation keeps SAA high: rheumatoid arthritis, IBD, chronic infections (TB, osteomyelitis, bronchiectasis), and familial Mediterranean fever, in which colchicine helps prevent amyloid. The kidney is the dominant target.

Dialysis-related amyloidosis. β2-microglobulin, the light chain of MHC class I, is normally cleared by the kidney but is not removed by older dialysis membranes, so it accumulates over years. It deposits in joints, tendons, and bone, classically causing bilateral carpal tunnel syndrome and a destructive arthropathy (e.g., of the shoulder).

ATTR amyloidosis. Fibrils are transthyretin (prealbumin), a liver-made carrier of thyroxine and retinol. Two forms: hereditary (mutant TTR, e.g., V122I in about 4% of Black Americans), causing cardiomyopathy and/or polyneuropathy; and senile, wild-type ATTR, which deposits slowly in the hearts of older men (roughly 60-80 years) and is an under-recognized cause of restrictive heart failure.

Systemic amyloid types

Type	Precursor protein	Setting	Main targets
AL (primary)	Immunoglobulin light chains (often λ)	Myeloma, MGUS, other plasma cell dyscrasias	Heart, kidney, tongue, nerves, skin
AA (secondary)	Serum amyloid A	RA, IBD, TB, osteomyelitis, bronchiectasis, FMF	Kidney (also liver, spleen)
Dialysis-related	β2-microglobulin	Long-term hemodialysis	Tendons, joints, bone (carpal tunnel)
Hereditary ATTR	Mutant transthyretin	Inherited TTR mutation (e.g., V122I)	Heart, peripheral and autonomic nerves
Wild-type ATTR	Normal transthyretin	Older men	Heart

Localized amyloid

Aβ and the brain. Amyloid β is cleaved from amyloid precursor protein (APP), encoded on chromosome 21. It forms neuritic plaques in Alzheimer disease, which is why trisomy 21 (an extra APP copy) causes early Alzheimer pathology. Aβ in cerebral vessel walls is cerebral amyloid angiopathy, a cause of lobar intracerebral hemorrhage in the elderly.

Organ-restricted amyloids

Protein	Site	Disease
Amyloid β (from APP)	Brain parenchyma, cerebral vessels	Alzheimer disease; cerebral amyloid angiopathy
Islet amyloid polypeptide (amylin)	Pancreatic islets	Type 2 diabetes
Calcitonin (A-Cal)	Thyroid tumor stroma	Medullary thyroid carcinoma
ANP	Atria	Isolated atrial amyloid

Organ involvement and clinical clues

Kidney. The most commonly involved organ overall. Glomerular deposits cause heavy proteinuria and nephrotic syndrome and can progress to renal failure. Suspect amyloid when nephrotic proteinuria accompanies a plasma cell disorder or a chronic inflammatory disease.

Heart. Interstitial deposits thicken and stiffen the ventricular walls, producing a restrictive (infiltrative) cardiomyopathy with diastolic heart failure. The classic paradox: thick walls on echo (with a speckled, granular myocardium) but LOW voltage on ECG, because amyloid is electrically inert. Cardiac involvement drives prognosis in AL.

Interstitial amyloidMyocardium infiltrated
Walls thicken and stiffenRestrictive cardiomyopathy
Impaired fillingDiastolic heart failure
Low-voltage ECGDespite thick walls on echo

Cardiac amyloidosis

AL-specific clues. Macroglossia (enlarged tongue) and periorbital purpura ("raccoon eyes" from fragile, amyloid-laden vessels) are near-specific for AL. Other findings: waxy skin, hepatomegaly, easy bruising, and autonomic and peripheral neuropathy (including carpal tunnel syndrome). Amyloid can bind and deplete factor X, adding an acquired bleeding tendency.

Spleen and liver. Splenic deposits may be nodular in the follicles ("sago spleen") or diffuse in the red pulp ("lardaceous spleen"); hepatic deposits cause hepatomegaly.

Diagnosis and treatment

Biopsy first. Sample the abdominal fat pad, rectum, or the affected organ. Congo red staining shows apple-green birefringence under polarized light.

Identify the precursor. Serum and urine free light chains with immunofixation identify an AL clone; tissue typing (mass spectrometry) confirms the precursor protein, which matters because an elderly patient with a light-chain abnormality may still have wild-type ATTR.

Treat the source. Chemotherapy against the plasma cell clone for AL; control of the underlying inflammation for AA (e.g., colchicine in familial Mediterranean fever); newer dialysis membranes reduce β2-microglobulin retention.

Myeloma + nephrotic syndrome + big tongue = AL (light chains). Long-standing RA + proteinuria = AA (SAA). Dialysis + carpal tunnel = β2-microglobulin. Elderly man + thick-walled heart + low voltage = wild-type ATTR.