Makindo Medical Notes

Key fact: A negative biopsy does not exclude amyloidosis, as deposition is often patchy. The exception is cardiac amyloidosis, where disease is usually widespread if echo changes are present.

About

• Amyloid is an abnormal, insoluble protein with a beta-pleated sheet structure.
• Deposits accumulate within tissues and cannot be broken down, causing progressive organ dysfunction.
• Amyloid is derived from smaller precursor proteins (e.g. immunoglobulin light chain, serum amyloid A, transthyretin).

Pathology

• Congo red stain with apple-green birefringence on polarised light is diagnostic.
• Electron microscopy: non-branching fibrils, 7.5–10 nm in diameter.
• β2-microglobulin amyloid occurs in long-term dialysis → carpal tunnel, osteoarticular disease.
• Amyloid is resistant to macrophage digestion, explaining progressive accumulation.

Major Types

Type	Clinical Notes
Primary (AL)	Light chain amyloid, associated with myeloma, Waldenström’s, MGUS. Features: restrictive cardiomyopathy, nephrotic syndrome, macroglossia, periorbital purpura. Worse prognosis if myeloma present.
Secondary (AA)	Serum amyloid A protein; seen in chronic inflammation (RA, bronchiectasis, TB, FMF). Presents mainly with nephrotic syndrome. Cardiac/tongue involvement is rare.
Familial (ATTR)	Transthyretin amyloid. Hereditary forms cause neuropathy ± cardiac/renal disease. Wild-type ATTR causes age-related “senile” cardiac amyloidosis.
Dialysis-related (β2M)	Occurs in patients on long-term haemodialysis. Causes carpal tunnel syndrome and destructive arthropathy.

Clinical Red Flags 🚩

• Nephrotic syndrome and heavy proteinuria
• Autonomic neuropathy (e.g. postural hypotension, diarrhoea)
• Carpal tunnel syndrome (esp. bilateral, recurrent)
• Peripheral neuropathy, neuropathic pain
• Macroglossia, periorbital purpura
• Bleeding tendency (cutaneous, GI)
• Cachexia, hepatosplenomegaly, family history
• Cardiac disease: restrictive cardiomyopathy, heart failure, atrial arrhythmias, syncope, pleural/pericardial effusions

Investigations

• Basic: FBC, ESR, U&E, calcium, LFTs (low albumin, raised bilirubin)
• Myeloma screen: SPEP/UPEP, free light chains, skeletal survey or CT
• Tissue biopsy: subcutaneous fat, rectal mucosa, renal/heart. Congo red positive.
• Amyloid typing: immunohistochemistry, proteomics, DNA (for ATTR mutations)
• Imaging: echocardiogram (thickened myocardium, speckled pattern, restrictive filling), CT for organomegaly
• Nerve conduction & autonomic testing if neuropathy suspected

Management

• Supportive: diuretics for cardiac failure, nutritional support, analgesia
• AL amyloidosis: chemotherapy for plasma cell clone (e.g. bortezomib-based regimens)
• AA amyloidosis: control underlying inflammation (e.g. biologics in RA, treat infection)
• ATTR amyloidosis: liver transplant (hereditary); tafamidis and other stabilisers now available
• β2M amyloidosis: renal transplant if suitable

Cases — Systemic Amyloidosis

• Case 1 — Renal disease 🧪: A 59-year-old man with a 15-year history of rheumatoid arthritis presents with ankle swelling, frothy urine, and fatigue. Urine dip: 4+ protein, with nephrotic range proteinuria. Serum albumin 22 g/L. Renal biopsy shows AA amyloid deposition with Congo red staining. Diagnosis: secondary (AA) amyloidosis complicating chronic inflammation.
• Case 2 — Cardiac involvement ❤️: A 72-year-old woman with MGUS presents with progressive exertional breathlessness, syncope, and peripheral oedema. Echocardiogram: restrictive cardiomyopathy with increased LV wall thickness and "sparkling" myocardium. Rectal biopsy confirms AL amyloidosis. Diagnosis: primary (AL) amyloidosis with cardiac involvement.
• Case 3 — Neuropathy and systemic disease 🧠: A 46-year-old man of Portuguese ancestry reports progressive numbness in feet, orthostatic dizziness, and weight loss. Exam: peripheral neuropathy, postural hypotension, hepatomegaly. Genetic testing reveals transthyretin mutation. Diagnosis: familial (ATTR) amyloidosis.

Teaching Point 🩺: Systemic amyloidosis may present in diverse ways — nephrotic syndrome, restrictive cardiomyopathy, or neuropathy. Always consider amyloid in unexplained multi-organ disease, especially with "red flag" signs such as macroglossia, periorbital purpura, or family history.