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PA9.1-2 | Amyloidosis — SDL Guide (Part 2)

Organ Involvement and Clinical Consequences

Amyloid deposits between and around cells, causing progressive pressure atrophy and vascular compromise. The organs most affected and the consequences vary by amyloid type.

Diagram showing systemic amyloidosis affecting kidney, heart, liver, spleen, gastrointestinal tract, tongue, and peripheral nerves with major clinical consequences. — **Panel A:** Anterior body outline showing kidney, heart, liver, spleen, GI tract and tongue, and peripheral nerves with organ-specific amyloid involvement callouts.. **Panel B:** Kidney cut surface and glomerulus showing amyloid in glomerular mesangium and basement membrane causing nephrotic syndrome, chronic kidney disease, and end-stage renal failure; AA and AL types.. **Panel C:** Heart cross-section showing myocardial interstitial and vessel wall amyloid causing restrictive cardiomyopathy, diastolic heart failure, conduction defects, and ECG-echo mismatch; AL and ATTR types.. **Panel D:** Liver and spleen showing amyloid in space of Disse with hepatomegaly and splenic lardaceous and sago patterns.. **Panel E:** GI tract and tongue showing macroglossia, intestinal amyloid deposits, and malabsorption.. **Panel F:** Peripheral nerve fascicle showing amyloid-related vascular compromise, pressure atrophy, and neuropathy..

Kidney — the most commonly affected and the leading cause of death in systemic amyloidosis

Deposits in glomerular mesangium and basement membrane → obliterates filtration surface
Clinically: nephrotic syndrome (massive proteinuria, hypoalbuminaemia, oedema) → progressive chronic kidney disease → end-stage renal failure
Gross: enlarged, pale, firm, waxy-cut-surface kidneys
AA and AL types both devastate the kidney

Heart

Deposits in myocardial interstitium and vessel walls → restrictive cardiomyopathy
Clinically: diastolic heart failure, conduction defects (heart block), low-voltage ECG pattern despite echocardiographic hypertrophy — a classic ECG-echo mismatch
Echocardiography: granular sparkling pattern, thickened walls, small ventricular cavity
AL and senile ATTR primarily

Liver and Spleen

Liver: deposits in space of Disse → hepatomegaly, mild liver dysfunction (jaundice rare)
Spleen: two patterns:
Sago spleen — deposits in follicles → tapioca-grain appearance
Lardaceous spleen — diffuse deposits in red pulp → homogeneous, lard-like cut surface
Clinically: splenomegaly, hyposplenism (functional asplenia risk)

Gastrointestinal Tract

Tongue: macroglossia — hallmark of AL; firm, rubbery enlargement
Wall deposits → dysmotility, malabsorption, protein-losing enteropathy
Submucosal deposits → "accordion" mucosal folds on endoscopy

Peripheral and Autonomic Nerves

Deposits compress nerve fibres → sensorimotor peripheral neuropathy (painful, length-dependent)
Autonomic neuropathy: postural hypotension, impotence, bladder dysfunction
Prominent in familial ATTR and AL

Other sites: adrenal (adrenal insufficiency), skin (waxy papules in AL), joints (amyloid arthropathy)

CLINICAL PEARL

The ECG-echo mismatch in cardiac amyloid: In most causes of left ventricular hypertrophy (hypertension, aortic stenosis), ECG shows high-voltage QRS complexes. In amyloid cardiomyopathy, the thickened walls on echo are filled with amyloid (electrically inert), so the ECG shows low voltage or a pseudo-infarct pattern. This dissociation between echo wall thickness and ECG voltage is a red-flag sign for cardiac amyloid.

Macroglossia is not caused by muscle hypertrophy — it is amyloid infiltration of the tongue stroma. It is virtually pathognomonic of systemic AL amyloidosis when found in an adult.

Morphology — Gross and Microscopic Features

Gross morphology:

Affected organs are typically:
• Enlarged, firm, and pale
• Cut surface has a waxy, translucent appearance — described historically as "lardaceous" (lard-like)
• Iodine reaction: Lugol's iodine stains amyloid brown; dilute H₂SO₄ turns it blue-violet (mahogany colour)
• Spleen shows sago (follicular) or lardaceous (diffuse) patterns as above

Microscopic morphology (H&E):

Amyloid appears as amorphous, homogeneous, eosinophilic, hyaline extracellular material
Deposits around small blood vessels, between cells, and in basement membranes
No cellular inflammatory response in established deposits (unlike acute inflammation)
Over time, adjacent parenchymal cells undergo pressure atrophy — functional tissue is replaced by inert protein

Special stain — Congo red (the gold standard):

Congo red on standard light microscopy: salmon-pink staining of deposits
Congo red under crossed polarised light: apple-green birefringence — pathognomonic
Sensitivity ~85%, specificity ~97% when birefringence is assessed by an experienced observer

Four-panel medical diagram showing gross waxy amyloid organs, renal H&E amyloid deposits, Congo red birefringence, and electron microscopic fibrils. — **Panel A:** Gross amyloidosis showing enlarged firm pale kidney and spleen, waxy translucent lardaceous cut surface, sago spleen follicular deposits, lardaceous spleen diffuse deposits, Lugol iodine brown reaction, dilute H2SO4 blue-violet reaction.. **Panel B:** H&E renal amyloidosis showing amorphous homogeneous eosinophilic extracellular amyloid deposits in glomerular mesangium and interstitium, perivascular deposits, basement membrane deposits, compressed renal tubules, pressure atrophy, no inflammatory response.. **Panel C:** Congo red special stain showing salmon-pink amyloid deposits on light microscopy and apple-green birefringence under crossed polarized light.. **Panel D:** Electron microscopy showing randomly arranged non-branching amyloid fibrils measuring 7.5–10 nm in diameter..

Electron microscopy (research/reference labs):
• Non-branching fibrils, 7.5–10 nm diameter, randomly arranged
• P component seen as pentagonal structures associated with fibrils

Diagnosis — Biopsy Strategies

Diagram showing the diagnostic pathway for systemic amyloidosis, emphasizing biopsy site selection, Congo red confirmation, and amyloid typing. — **Panel A:** Diagnostic pathway showing clinical suspicion, supportive imaging by echocardiography or SAP/DPD scintigraphy, mandatory tissue biopsy, Congo red confirmation, and amyloid typing.. **Panel B:** Preferred biopsy sites for systemic amyloidosis: abdominal fat pad aspiration approximately 80% sensitivity, rectal submucosal biopsy approximately 75-80%, bone marrow biopsy approximately 60-70%, and affected organ biopsy greater than 90% yield.. **Panel C:** Histological confirmation showing Congo red-positive extracellular amyloid deposits and apple-green birefringence under polarized light.. **Panel D:** Typing after diagnosis showing immunohistochemistry, immunofluorescence, laser microdissection with mass spectrometry, and serum or urine testing for monoclonal protein in AL amyloidosis..

Tissue biopsy is mandatory for definitive diagnosis. Imaging (echocardiography, nuclear scintigraphy with SAP or DPD) can suggest the diagnosis and help with typing, but histological confirmation with Congo red is required.

Preferred biopsy sites (systemic amyloidosis):

Site	Yield	Notes
Abdominal fat pad aspiration	~80% sensitivity	Least invasive; first choice in suspected systemic disease
Rectal biopsy (submucosal)	~75–80%	Good alternative; submucosal vessels consistently involved
Bone marrow biopsy	~60–70%	Simultaneously assesses plasma cell burden in AL
Affected organ (kidney, liver, heart)	>90%	Highest yield but most invasive; used when above are negative

Typing after diagnosis:

Immunohistochemistry (anti-κ, anti-λ, anti-SAA, anti-TTR) — widely available; AL can be difficult
Laser microdissection + mass spectrometry — gold standard for protein typing; resolves difficult cases
Serum/urine studies: SPEP, UPEP, serum free light chains → plasma cell dyscrasia
Genetic testing: for ATTR mutations in familial disease
SAP scintigraphy — whole-body amyloid load and distribution (not available everywhere)

Practical point: Abdominal fat pad + bone marrow together achieve ~90% sensitivity for systemic AL — non-invasively sufficient to start treatment in most patients.

SELF-CHECK

At autopsy, a 70-year-old man's spleen is enlarged and shows scattered, translucent, tapioca-grain–like deposits in the white pulp on cut section. Which pattern of splenic amyloidosis does this describe?

A. Lardaceous spleen — diffuse deposits in the red pulp

B. Sago spleen — deposits confined to the follicles

C. Amyloid angiopathy — deposits in splenic artery walls only

D. Infiltrative pattern — deposits in the capsule and trabeculae

Reveal Answer

Answer: B. Sago spleen — deposits confined to the follicles

Sago spleen is the follicular pattern — amyloid deposits in the white pulp (follicles), producing discrete, translucent grey nodules resembling sago or tapioca pearls. Lardaceous spleen (option A) describes the diffuse red-pulp pattern, which produces a homogeneous, lard-like, grey-white cut surface. Both patterns can coexist in advanced disease.